6-152337007-T-C

Variant names:

• chr6-152337007-T-C
• rs9479297
• NM_182961.4:c.12362A>G

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.12362A>G​(p.Lys4121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 1,613,086 control chromosomes in the GnomAD database, including 460,415 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K4121S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.80 (49061 hom., cov: 31)
  • Exomes 𝑓: 0.75 (411354 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.50
• Publications: 38 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: G2P, Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, 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: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• 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=1.0020265E-6).
• BP6: Variant 6-152337007-T-C is Benign according to our data. Variant chr6-152337007-T-C is described in ClinVar as Benign. ClinVar VariationId is 130399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.12362A>G	p.Lys4121Arg	missense	Exon 76 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.12149A>G	p.Lys4050Arg	missense	Exon 75 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.12362A>G	p.Lys4121Arg	missense	Exon 76 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.12149A>G	p.Lys4050Arg	missense	Exon 75 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000471834.1	TSL:1	n.5500A>G		non_coding_transcript_exon	Exon 19 of 19

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121340 AN: 152050 Hom.: 48994 Cov.: 31

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.754

GnomAD2 exomes AF: 0.749 AC: 187478 AN: 250188 AF XY: 0.740

Gnomad AFR exome AF: 0.932

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.699

Gnomad EAS exome AF: 0.855

Gnomad FIN exome AF: 0.836

Gnomad NFE exome AF: 0.746

Gnomad OTH exome AF: 0.741

GnomAD4 exome AF: 0.748 AC: 1093367 AN: 1460918 Hom.: 411354 Cov.: 55 AF XY: 0.744 AC XY: 540551 AN XY: 726756

African (AFR) AF: 0.933 AC: 31218 AN: 33472

American (AMR) AF: 0.703 AC: 31367 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 18303 AN: 26128

East Asian (EAS) AF: 0.860 AC: 34144 AN: 39694

South Asian (SAS) AF: 0.623 AC: 53709 AN: 86228

European-Finnish (FIN) AF: 0.829 AC: 43920 AN: 52992

Middle Eastern (MID) AF: 0.617 AC: 3559 AN: 5766

European-Non Finnish (NFE) AF: 0.749 AC: 832070 AN: 1111614

Other (OTH) AF: 0.747 AC: 45077 AN: 60376

GnomAD4 genome AF: 0.798 AC: 121469 AN: 152168 Hom.: 49061 Cov.: 31 AF XY: 0.798 AC XY: 59409 AN XY: 74404

African (AFR) AF: 0.929 AC: 38588 AN: 41526

American (AMR) AF: 0.725 AC: 11071 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2377 AN: 3466

East Asian (EAS) AF: 0.848 AC: 4387 AN: 5174

South Asian (SAS) AF: 0.625 AC: 3013 AN: 4822

European-Finnish (FIN) AF: 0.832 AC: 8814 AN: 10596

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50792 AN: 68000

Other (OTH) AF: 0.757 AC: 1595 AN: 2106

Alfa AF: 0.758 Hom.: 115891

Bravo AF: 0.798

TwinsUK AF: 0.740 AC: 2744

ALSPAC AF: 0.758 AC: 2920

ESP6500AA AF: 0.922 AC: 4064

ESP6500EA AF: 0.719 AC: 6187

ExAC AF: 0.751 AC: 91225

Asia WGS AF: 0.772 AC: 2687 AN: 3478

EpiCase AF: 0.725

EpiControl AF: 0.727

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Autosomal recessive ataxia, Beauce type (2)
-	-	2	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (2)
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.081
MPC		0.11
ClinPred		0.0015	T
GERP RS		4.5
Varity_R		0.035
gMVP		0.16
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: rs9479297; hg19: chr6-152658142; COSMIC: COSV54950715; COSMIC: COSV54950715;