6-152146308-A-G

Variant names:

• chr6-152146308-A-G
• rs2673790
• NM_182961.4:c.24976+1737T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182961.4(SYNE1):​c.24976+1737T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 152,096 control chromosomes in the GnomAD database, including 8,887 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (8887 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.112
• 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

ENSG00000300811 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.24976+1737T>C		intron	N/A	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.1442-753T>C		intron	N/A	NP_001334631.1
	SYNE1	NM_033071.5		c.24764-753T>C		intron	N/A	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.24976+1737T>C		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.1442-753T>C		intron	N/A	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.24764-753T>C		intron	N/A	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51229 AN: 151968 Hom.: 8881 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.100 AC: 1 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 1 AN XY: 8

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.337 AC: 51270 AN: 152086 Hom.: 8887 Cov.: 32 AF XY: 0.338 AC XY: 25117 AN XY: 74348

African (AFR) AF: 0.336 AC: 13926 AN: 41498

American (AMR) AF: 0.458 AC: 6991 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3472

East Asian (EAS) AF: 0.312 AC: 1620 AN: 5186

South Asian (SAS) AF: 0.399 AC: 1923 AN: 4816

European-Finnish (FIN) AF: 0.216 AC: 2285 AN: 10576

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21936 AN: 67968

Other (OTH) AF: 0.385 AC: 812 AN: 2110

Alfa AF: 0.350 Hom.: 4011

Bravo AF: 0.357

Asia WGS AF: 0.345 AC: 1196 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.59
PhyloP100		-0.11
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: rs2673790; hg19: chr6-152467443; COSMIC: COSV54938444; COSMIC: COSV54938444;