rs138787771

Variant names:

• chr6-152180281-C-T
• rs138787771
• NM_182961.4:c.23315G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_182961.4(SYNE1):​c.23315G>A​(p.Arg7772Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,613,974 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7772W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (48 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 2.55
• Publications: 7 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00968194).
• BP6: Variant 6-152180281-C-T is Benign according to our data. Variant chr6-152180281-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 48 AD,AR 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.23315G>A	p.Arg7772Gln	missense	Exon 129 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.23102G>A	p.Arg7701Gln	missense	Exon 128 of 146	NP_149062.2	Q8NF91-4
	SYNE1	NM_001347701.2		c.-80G>A		5_prime_UTR	Exon 2 of 18	NP_001334630.1	B7Z9Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.23315G>A	p.Arg7772Gln	missense	Exon 129 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.23102G>A	p.Arg7701Gln	missense	Exon 128 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367251.7	TSL:1	c.2081G>A	p.Arg694Gln	missense	Exon 14 of 31	ENSP00000356220.3	H0Y325

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152104 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00351 AC: 881 AN: 250934 AF XY: 0.00363

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00641

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00645 AC: 9435 AN: 1461752 Hom.: 48 Cov.: 32 AF XY: 0.00623 AC XY: 4529 AN XY: 727178

African (AFR) AF: 0.00111 AC: 37 AN: 33478

American (AMR) AF: 0.000984 AC: 44 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86252

European-Finnish (FIN) AF: 0.00157 AC: 84 AN: 53398

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00794 AC: 8834 AN: 1111946

Other (OTH) AF: 0.00503 AC: 304 AN: 60390

GnomAD4 genome AF: 0.00415 AC: 631 AN: 152222 Hom.: 1 Cov.: 31 AF XY: 0.00372 AC XY: 277 AN XY: 74414

African (AFR) AF: 0.00149 AC: 62 AN: 41522

American (AMR) AF: 0.00222 AC: 34 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000944 AC: 10 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00693 AC: 471 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00565 Hom.: 8

Bravo AF: 0.00428

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00371 AC: 450

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	3	not specified (4)
-	-	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)
-	-	1	SYNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.5
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.96	P
Vest4		0.22
MVP		0.43
MPC		0.16
ClinPred		0.045	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.28
Mutation Taster		=92/8	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs138787771; hg19: chr6-152501416;