6-152148298-G-T

Variant names:

• chr6-152148298-G-T
• rs141586001
• NM_182961.4:c.24723C>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_182961.4(SYNE1):​c.24723C>A​(p.His8241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000039 (0 hom., cov: 32)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03009069).
• BS2: High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.24723C>A	p.His8241Gln	missense_variant	Exon 137 of 146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.1188C>A	p.His396Gln	missense_variant	Exon 8 of 18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.24723C>A	p.His8241Gln	missense_variant	Exon 137 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.1188C>A	p.His396Gln	missense_variant	Exon 8 of 18	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250554 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135382

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0050
DANN	Benign	0.60
DEOGEN2	Benign	0.27	T;.;.;T;T;T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.63	T;T;T;T;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.030	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N;.;N;N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.36	T;.;T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.;.
Vest4		0.080
MutPred		0.25		Loss of catalytic residue at H8241 (P = 0.199);.;.;.;.;.;.;
MVP		0.27
MPC		0.13
ClinPred		0.041	T
GERP RS		-11
Varity_R		0.026
gMVP		0.24

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs141586001; hg19: chr6-152469433;