6-152218380-G-C

Variant names:

• chr6-152218380-G-C
• rs35686213
• NM_182961.4:c.22068C>G
• SYNE1 p.Thr7356Thr

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP7

The NM_182961.4(SYNE1):c.22068C>G (p.Thr7356Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.475
• Publications: 0 publications found

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics, Orphanet
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000125 by highest known P/LP ClinVar AF 0.000125) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Moderate).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_182961.4. 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
	SYNE1 NM_182961.4	MANE Select	c.22068C>G p.Thr7356Thr	synonymous	Exon 121 of 146	Prot: NP_892006.3 UniProt:
	SYNE1 NM_033071.5		c.21855C>G p.Thr7285Thr	synonymous	Exon 120 of 146	Prot: NP_149062.2 UniProt:

SYNE1 NM_182961.4

MANE Select

HGVSc / HGVSpc.22068C>Gp.Thr7356Thr

Exon rankExon 121 of 146

synonymous

Prot: NP_892006.3UniProt: Q8NF91-1

SYNE1 NM_033071.5

HGVSc / HGVSpc.21855C>Gp.Thr7285Thr

Exon rankExon 120 of 146

synonymous

Prot: NP_149062.2UniProt: A0A0C4DG40Q8NF91-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SYNE1 ENST00000367255.10	TSL:1MANE Select	c.22068C>G p.Thr7356Thr	synonymous	Exon 121 of 146	Prot: ENSP00000356224.5 UniProt:
	SYNE1 ENST00000423061.6	TSL:1	c.21855C>G p.Thr7285Thr	synonymous	Exon 120 of 146	Prot: ENSP00000396024.1 UniProt:
	SYNE1 ENST00000367251.7	TSL:1	c.834C>G p.Thr278Thr	synonymous	Exon 6 of 31	Prot: ENSP00000356220.3 UniProt:

SYNE1 ENST00000367255.10

TSL:1MANE Select

HGVSc / HGVSpc.22068C>Gp.Thr7356Thr

Exon rankExon 121 of 146

synonymous

Prot: ENSP00000356224.5UniProt: Q8NF91-1

SYNE1 ENST00000423061.6

TSL:1

HGVSc / HGVSpc.21855C>Gp.Thr7285Thr

Exon rankExon 120 of 146

synonymous

Prot: ENSP00000396024.1UniProt: A0A0C4DG40

SYNE1 ENST00000367251.7

TSL:1

HGVSc / HGVSpc.834C>Gp.Thr278Thr

Exon rankExon 6 of 31

synonymous

Prot: ENSP00000356220.3UniProt: H0Y325

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.2
DANN	Benign	0.64
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
PhyloP100	Benign	-0.47
PromoterAI	N/A	0.017	Neutral

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 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: rs35686213;

hg19: chr6-152539515;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar