rs9371243

Variant names:

• chr6-152218215-C-G
• rs9371243
• NM_182961.4:c.22191+42G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.22191+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,608,724 control chromosomes in the GnomAD database, including 47,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4014 hom., cov: 30)
  • Exomes 𝑓: 0.23 (43843 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.674
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-152218215-C-G is Benign according to our data. Variant chr6-152218215-C-G is described in ClinVar as Benign. ClinVar VariationId is 262183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.22191+42G>C		intron_variant	Intron 121 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.22191+42G>C		intron_variant	Intron 121 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31958 AN: 151654 Hom.: 4012 Cov.: 30

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.265 AC: 66404 AN: 250676 AF XY: 0.267

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.571

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.235 AC: 342126 AN: 1456952 Hom.: 43843 Cov.: 33 AF XY: 0.236 AC XY: 171261 AN XY: 725080

African (AFR) AF: 0.112 AC: 3747 AN: 33352

American (AMR) AF: 0.247 AC: 11011 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6875 AN: 26064

East Asian (EAS) AF: 0.526 AC: 20861 AN: 39634

South Asian (SAS) AF: 0.317 AC: 27239 AN: 86004

European-Finnish (FIN) AF: 0.341 AC: 18157 AN: 53304

Middle Eastern (MID) AF: 0.103 AC: 591 AN: 5756

European-Non Finnish (NFE) AF: 0.216 AC: 239182 AN: 1108012

Other (OTH) AF: 0.240 AC: 14463 AN: 60168

GnomAD4 genome AF: 0.211 AC: 31976 AN: 151772 Hom.: 4014 Cov.: 30 AF XY: 0.221 AC XY: 16345 AN XY: 74116

African (AFR) AF: 0.117 AC: 4860 AN: 41436

American (AMR) AF: 0.192 AC: 2927 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 932 AN: 3464

East Asian (EAS) AF: 0.548 AC: 2794 AN: 5098

South Asian (SAS) AF: 0.347 AC: 1672 AN: 4816

European-Finnish (FIN) AF: 0.354 AC: 3711 AN: 10488

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14457 AN: 67926

Other (OTH) AF: 0.186 AC: 390 AN: 2102

Alfa AF: 0.213 Hom.: 677

Bravo AF: 0.197

Asia WGS AF: 0.406 AC: 1413 AN: 3478

ClinVar

Significance: 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.021
DANN	Benign	0.57
PhyloP100		-0.67
PromoterAI		0.0012	Neutral
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: rs9371243; hg19: chr6-152539350; COSMIC: COSV54896874;