NM_182961.4:c.22068C>T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_ModerateBP6BP7

The NM_182961.4(SYNE1):c.22068C>T (p.Thr7356Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00153 (AC=2,470) in the gnomAD database across 1,613,228 control chromosomes, including 5 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0018. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -0.475
• Publications: 3 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: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).
	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).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 5.; Very high cumulative gnomAD AC = 2470 (any gene).

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>T	p.Thr7356Thr	synonymous	Exon 121 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.21855C>T	p.Thr7285Thr	synonymous	Exon 120 of 146	NP_149062.2	A0A0C4DG40

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.22068C>T	p.Thr7356Thr	synonymous	Exon 121 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.21855C>T	p.Thr7285Thr	synonymous	Exon 120 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367251.7	TSL:1	c.834C>T	p.Thr278Thr	synonymous	Exon 6 of 31	ENSP00000356220.3	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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00107	AC:162	Hom:1	AN:151328	Cov:31
GnomAD2 exomes	AF: 0.000971	AC:244	Hom:	AN:251248	Cov:
GnomAD4 exome	AF: 0.00158	AC:2308	Hom:4	AN:1461786	Cov:35
GnomAD4 genome	AF: 0.00107	AC:162	Hom:1	AN:151442	Cov:31
TOPMed (Bravo)	AF: 0.00119	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00108	AC:106	Hom:0	AN:98078	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00154	AC:20	Hom:	AN:13006	Cov:
Korea4K (4,157 Koreans)	AF: 0.00359	AC:26	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00193	AC:237	Hom:2	AN:122528	Cov:
Turkish Variome	AF: 0.000298	AC:2	Hom:0	AN:6716	Cov:
UK10K	AF: 0.00159	AC:12	Hom:	AN:7562	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000900 *	10	11112	0.00136 *	24	17612
BipEx(Bipolar disorder (including schizoaffective))	0.00144	41	28420	0.00156	45	28844
Epi25(Epilepsy)	0.00112	47	41956	0.00139	93	66878
SCHEMA(Schizophrenia)	0.00112	129	114676	0.00112	196	175350

Showing 4 cohortsAllele 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
-	1	3	not provided (4)
-	-	2	not specified (2)
-	1	-	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.0
DANN	Benign	0.63
GPN-Star LLR	N/A	-2.0
GPN-Star score	N/A	2.0
Mutation Taster	N/A	97/3	polymorphism
PhyloP100	Benign	-0.47
PromoterAI	N/A	-0.033	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040

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.

Other links and lift over

dbSNP: rs35686213;

hg19: chr6-152539515;

COSMIC: COSV99556987;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar