6-152236976-TA-TAA

Variant names:

• chr6-152236976-T-TA
• rs36215566
• NM_182961.4:c.20068-29dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.20068-29dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,611,122 control chromosomes in the GnomAD database, including 39,899 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3550 hom., cov: 28)
  • Exomes 𝑓: 0.22 (36349 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.407
• 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: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-152236976-T-TA is Benign according to our data. Variant chr6-152236976-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.20068-29dupT		intron_variant	Intron 108 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.20068-29_20068-28insT		intron_variant	Intron 108 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.19855-29_19855-28insT		intron_variant	Intron 107 of 145	1		ENSP00000396024.1
SYNE1	ENST00000367256.9	n.3760-29_3760-28insT		intron_variant	Intron 23 of 60	1
SYNE1	ENST00000409694.6	n.3652-29_3652-28insT		intron_variant	Intron 21 of 58	1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29807 AN: 151958 Hom.: 3542 Cov.: 28

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.243 AC: 59990 AN: 246790 AF XY: 0.237

Gnomad AFR exome AF: 0.0769

Gnomad AMR exome AF: 0.451

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.217 AC: 317291 AN: 1459046 Hom.: 36349 Cov.: 32 AF XY: 0.217 AC XY: 157444 AN XY: 725758

African (AFR) AF: 0.0764 AC: 2556 AN: 33460

American (AMR) AF: 0.440 AC: 19502 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4649 AN: 26094

East Asian (EAS) AF: 0.236 AC: 9346 AN: 39600

South Asian (SAS) AF: 0.217 AC: 18646 AN: 86018

European-Finnish (FIN) AF: 0.262 AC: 13872 AN: 52956

Middle Eastern (MID) AF: 0.233 AC: 1269 AN: 5448

European-Non Finnish (NFE) AF: 0.211 AC: 234501 AN: 1110896

Other (OTH) AF: 0.215 AC: 12950 AN: 60282

GnomAD4 genome AF: 0.196 AC: 29839 AN: 152076 Hom.: 3550 Cov.: 28 AF XY: 0.202 AC XY: 15030 AN XY: 74328

African (AFR) AF: 0.0792 AC: 3286 AN: 41512

American (AMR) AF: 0.361 AC: 5509 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 622 AN: 3468

East Asian (EAS) AF: 0.226 AC: 1163 AN: 5156

South Asian (SAS) AF: 0.225 AC: 1083 AN: 4816

European-Finnish (FIN) AF: 0.257 AC: 2710 AN: 10554

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14775 AN: 67988

Other (OTH) AF: 0.214 AC: 452 AN: 2112

Alfa AF: 0.151 Hom.: 437

Asia WGS AF: 0.243 AC: 846 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs36215566; hg19: chr6-152558111; COSMIC: COSV99585534;