NM_182961.4:c.4757C>A

Variant names:

• chr6-152430143-G-T
• rs77675624
• NM_182961.4:c.4757C>A
• SYNE1 p.Thr1586Lys

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.4757C>A​(p.Thr1586Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00443 in 1,602,944 control chromosomes in the GnomAD database, including 168 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1586A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (148 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.38
• Publications: 10 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, Laboratory for Molecular Medicine
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=0.0025706887).
• BP6: Variant 6-152430143-G-T is Benign according to our data. Variant chr6-152430143-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.062 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.4757C>A	p.Thr1586Lys	missense	Exon 36 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.4778C>A	p.Thr1593Lys	missense	Exon 36 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.4757C>A	p.Thr1586Lys	missense	Exon 36 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.4778C>A	p.Thr1593Lys	missense	Exon 36 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000461872.6	TSL:1	n.4975C>A		non_coding_transcript_exon	Exon 34 of 55

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 952 AN: 152036 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0316

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0108 AC: 2573 AN: 238176 AF XY: 0.00897

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.0418

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.0351

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.000904

Gnomad OTH exome AF: 0.00767

GnomAD4 exome AF: 0.00424 AC: 6152 AN: 1450792 Hom.: 148 Cov.: 30 AF XY: 0.00406 AC XY: 2931 AN XY: 721104

African (AFR) AF: 0.000751 AC: 25 AN: 33310

American (AMR) AF: 0.0415 AC: 1836 AN: 44202

Ashkenazi Jewish (ASJ) AF: 0.00457 AC: 118 AN: 25832

East Asian (EAS) AF: 0.0640 AC: 2524 AN: 39416

South Asian (SAS) AF: 0.00366 AC: 311 AN: 85064

European-Finnish (FIN) AF: 0.0113 AC: 599 AN: 52826

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5722

European-Non Finnish (NFE) AF: 0.000426 AC: 471 AN: 1104592

Other (OTH) AF: 0.00440 AC: 263 AN: 59828

GnomAD4 genome AF: 0.00627 AC: 954 AN: 152152 Hom.: 20 Cov.: 33 AF XY: 0.00759 AC XY: 565 AN XY: 74396

African (AFR) AF: 0.00123 AC: 51 AN: 41534

American (AMR) AF: 0.0317 AC: 484 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.0371 AC: 192 AN: 5178

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.0111 AC: 117 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 67980

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00277 Hom.: 10

Bravo AF: 0.00809

Asia WGS AF: 0.0220 AC: 77 AN: 3462

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	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	0.20
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.047
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0060	D
Varity_R		0.27
gMVP		0.14
Mutation Taster		=90/10	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77675624;

hg19: chr6-152751278;

COSMIC: COSV55142609;

COSMIC: COSV55142609;