rs141716975

Variant names:

• chr6-152148069-G-A
• rs141716975
• NM_182961.4:c.24952C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152148069-G-A
• chr6-152148069-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_182961.4(SYNE1):​c.24952C>T​(p.Leu8318Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00575 in 1,614,084 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L8318R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (33 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 5.92
• Publications: 9 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

ENSG00000300811 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070774257).
• BP6: Variant 6-152148069-G-A is Benign according to our data. Variant chr6-152148069-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194303.
• BS2: High Homozygotes in GnomAdExome4 at 33 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.24952C>T	p.Leu8318Phe	missense	Exon 137 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.1417C>T	p.Leu473Phe	missense	Exon 8 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.24739C>T	p.Leu8247Phe	missense	Exon 136 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.24952C>T	p.Leu8318Phe	missense	Exon 137 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.1417C>T	p.Leu473Phe	missense	Exon 8 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.24739C>T	p.Leu8247Phe	missense	Exon 136 of 146	ENSP00000396024.1	A0A0C4DG40

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 152170 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00508 AC: 1269 AN: 249678 AF XY: 0.00527

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00590 AC: 8623 AN: 1461796 Hom.: 33 Cov.: 36 AF XY: 0.00592 AC XY: 4306 AN XY: 727192

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00188 AC: 84 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00746 AC: 195 AN: 26136

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39700

South Asian (SAS) AF: 0.00589 AC: 508 AN: 86250

European-Finnish (FIN) AF: 0.00519 AC: 277 AN: 53362

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00643 AC: 7149 AN: 1111982

Other (OTH) AF: 0.00575 AC: 347 AN: 60394

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152288 Hom.: 1 Cov.: 33 AF XY: 0.00415 AC XY: 309 AN XY: 74462

African (AFR) AF: 0.00118 AC: 49 AN: 41564

American (AMR) AF: 0.00281 AC: 43 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00669 AC: 455 AN: 68026

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00559 Hom.: 19

Bravo AF: 0.00377

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00530 AC: 643

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00581

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	2	Autosomal recessive ataxia, Beauce type (2)
-	-	2	not specified (2)
-	-	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	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.9
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.10	T
Polyphen		0.91	P
Vest4		0.48
MVP		0.55
MPC		0.32
ClinPred		0.046	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.29
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs141716975; hg19: chr6-152469204; COSMIC: COSV54958767;