rs79486252

Variant names:

• chr6-152354758-T-G
• rs79486252
• NM_182961.4:c.10827A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-152354758-T-G
• chr6-152354758-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182961.4(SYNE1):​c.10827A>C​(p.Gln3609His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,232 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (26 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0760
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003586948).
• BP6: Variant 6-152354758-T-G is Benign according to our data. Variant chr6-152354758-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 355888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00814 (1240/152340) while in subpopulation AFR AF = 0.0286 (1189/41570). AF 95% confidence interval is 0.0273. There are 19 homozygotes in GnomAd4. There are 594 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.10827A>C	p.Gln3609His	missense	Exon 67 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.10848A>C	p.Gln3616His	missense	Exon 67 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.10827A>C	p.Gln3609His	missense	Exon 67 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.10848A>C	p.Gln3616His	missense	Exon 67 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000471834.1	TSL:1	n.3965A>C		non_coding_transcript_exon	Exon 10 of 19

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1239 AN: 152222 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00203 AC: 511 AN: 251464 AF XY: 0.00155

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000767 AC: 1121 AN: 1461892 Hom.: 26 Cov.: 33 AF XY: 0.000635 AC XY: 462 AN XY: 727248

African (AFR) AF: 0.0295 AC: 989 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112012

Other (OTH) AF: 0.00156 AC: 94 AN: 60396

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152340 Hom.: 19 Cov.: 33 AF XY: 0.00797 AC XY: 594 AN XY: 74500

African (AFR) AF: 0.0286 AC: 1189 AN: 41570

American (AMR) AF: 0.00229 AC: 35 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00332 Hom.: 14

Bravo AF: 0.00873

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0320 AC: 141

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00273 AC: 331

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		-0.076
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.057
Sift	Benign	0.040	D
Sift4G	Benign	0.10	T
Polyphen		0.91	P
Vest4		0.11
MutPred		0.30		Loss of disorder (P = 0.073)
MVP		0.39
MPC		0.24
ClinPred		0.012	T
GERP RS		0.26
Varity_R		0.085
gMVP		0.21
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs79486252; hg19: chr6-152675893;