6-152442123-T-C

Variant names:

• chr6-152442123-T-C
• rs138705766
• NM_182961.4:c.3960A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182961.4(SYNE1):​c.3960A>G​(p.Thr1320Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,614,052 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (36 hom., cov: 33)
  • Exomes 𝑓: 0.016 (245 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.99
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-152442123-T-C is Benign according to our data. Variant chr6-152442123-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0177 (2697/152310) while in subpopulation NFE AF = 0.0204 (1386/68026). AF 95% confidence interval is 0.0195. There are 36 homozygotes in GnomAd4. There are 1388 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.3960A>G	p.Thr1320Thr	synonymous	Exon 31 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.3981A>G	p.Thr1327Thr	synonymous	Exon 31 of 146	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.3960A>G	p.Thr1320Thr	synonymous	Exon 31 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.3981A>G	p.Thr1327Thr	synonymous	Exon 31 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000461872.6	TSL:1	n.4178A>G		non_coding_transcript_exon	Exon 29 of 55

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2698 AN: 152192 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0186 AC: 4679 AN: 251042 AF XY: 0.0194

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0371

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0164 AC: 23962 AN: 1461742 Hom.: 245 Cov.: 32 AF XY: 0.0168 AC XY: 12181 AN XY: 727188

African (AFR) AF: 0.0106 AC: 354 AN: 33480

American (AMR) AF: 0.0112 AC: 503 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 954 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0200 AC: 1725 AN: 86256

European-Finnish (FIN) AF: 0.0318 AC: 1693 AN: 53282

Middle Eastern (MID) AF: 0.0338 AC: 195 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17433 AN: 1112006

Other (OTH) AF: 0.0183 AC: 1105 AN: 60392

GnomAD4 genome AF: 0.0177 AC: 2697 AN: 152310 Hom.: 36 Cov.: 33 AF XY: 0.0186 AC XY: 1388 AN XY: 74476

African (AFR) AF: 0.0102 AC: 426 AN: 41574

American (AMR) AF: 0.0182 AC: 279 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4830

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0204 AC: 1386 AN: 68026

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0178 Hom.: 8

Bravo AF: 0.0151

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.57
DANN	Benign	0.36
PhyloP100		-2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs138705766; hg19: chr6-152763258; COSMIC: COSV55119689;