NM_170707.4:c.346C>T

Variant names:

• chr1-156115264-C-T
• rs876657491
• NM_170707.4:c.346C>T
• LMNA p.Leu116Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingB4_Strong

The NM_170707.4(LMNA):c.346C>T (p.Leu116Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The gene LMNA is a known oncogene (CancerMine: 10 oncogene citations). The variant allele was found at a cumulative frequency of 0.00000756 (AC=11) in the gnomAD database across 1,455,286 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000262. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: LMNA NM_170707.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.09
• Publications: 1 publications found

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

LMNA Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, G2P
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• lipodystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Emery-Dreifuss muscular dystrophy 3, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mandibuloacral dysplasia with type A lipodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• atrial fibrillation

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• atypical Werner syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy due to LMNA mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal restrictive dermopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LMNA-related cardiocutaneous progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Emery-Dreifuss muscular dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal semi-dominant severe lipodystrophic laminopathy

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000003 — very rare (O3 supporting [+1])
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_170707.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LMNA NM_170707.4	MANE Select	c.346C>T p.Leu116Leu	synonymous	Exon 1 of 12	Prot: NP_733821.1 UniProt:
	LMNA NM_005572.4	MANE Plus Clinical	c.346C>T p.Leu116Leu	synonymous	Exon 1 of 10	Prot: NP_005563.1 UniProt:
	LMNA NM_001406986.1		c.-78C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	Prot: NP_001393915.1

LMNA NM_170707.4

MANE Select

HGVSc / HGVSpc.346C>Tp.Leu116Leu

Exon rankExon 1 of 12

synonymous

Prot: NP_733821.1UniProt: A0A384MQX1P02545-1

LMNA NM_005572.4

MANE Plus Clinical

HGVSc / HGVSpc.346C>Tp.Leu116Leu

Exon rankExon 1 of 10

synonymous

Prot: NP_005563.1UniProt: P02545-2

LMNA NM_001406986.1

HGVSc / HGVSpc.-78C>T

Exon rankExon 1 of 13

5_prime_UTR_premature_start_codon_gain

Prot: NP_001393915.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LMNA ENST00000368300.9	TSL:1MANE Select	c.346C>T p.Leu116Leu	synonymous	Exon 1 of 12	Prot: ENSP00000357283.4 UniProt:
	LMNA ENST00000677389.1	MANE Plus Clinical	c.346C>T p.Leu116Leu	synonymous	Exon 1 of 10	Prot: ENSP00000503633.1 UniProt:
	LMNA ENST00000368299.7	TSL:1	c.346C>T p.Leu116Leu	synonymous	Exon 1 of 12	Prot: ENSP00000357282.3 UniProt:

LMNA ENST00000368300.9

TSL:1MANE Select

HGVSc / HGVSpc.346C>Tp.Leu116Leu

Exon rankExon 1 of 12

synonymous

Prot: ENSP00000357283.4UniProt: P02545-1

LMNA ENST00000677389.1

MANE Plus Clinical

HGVSc / HGVSpc.346C>Tp.Leu116Leu

Exon rankExon 1 of 10

synonymous

Prot: ENSP00000503633.1UniProt: P02545-2

LMNA ENST00000368299.7

TSL:1

HGVSc / HGVSpc.346C>Tp.Leu116Leu

Exon rankExon 1 of 12

synonymous

Prot: ENSP00000357282.3UniProt: P02545-6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000425	AC:1	Hom:	AN:235102	Cov:
GnomAD4 exome	AF: 0.00000756	AC:11	Hom:0	AN:1455286	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
Turkish Variome	AF: 0.000363	AC:2	Hom:0	AN:5032	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	67726	0.00000752	1	132930

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.96
GPN-Star LLR	N/A	-2.8
GPN-Star score	N/A	2.8
Mutation Taster	N/A	36/64	disease causing
PhyloP100	Uncertain	4.1

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.12	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs876657491;

hg19: chr1-156085055;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar