rs946188918

Variant names:

• chr2-151499317-T-C
• rs946188918
• NM_001164507.2:c.24095A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001164508.2(NEB):​c.24095A>G​(p.Asn8032Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000438 in 1,371,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N8032K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.53
• Publications: 0 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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
	NEB	NM_001164507.2	MANE Plus Clinical	c.24095A>G	p.Asn8032Ser	missense	Exon 169 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24095A>G	p.Asn8032Ser	missense	Exon 169 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24200A>G	p.Asn8067Ser	missense	Exon 170 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.24095A>G	p.Asn8032Ser	missense	Exon 169 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24095A>G	p.Asn8032Ser	missense	Exon 169 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000688578.1		c.878A>G	p.Asn293Ser	missense	Exon 10 of 21	ENSP00000509628.1	A0A8I5KS37

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000438 AC: 6 AN: 1371406 Hom.: 0 Cov.: 26 AF XY: 0.00000444 AC XY: 3 AN XY: 676028

African (AFR) AF: 0.00 AC: 0 AN: 30476

American (AMR) AF: 0.00 AC: 0 AN: 32660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24478

East Asian (EAS) AF: 0.00 AC: 0 AN: 35132

South Asian (SAS) AF: 0.00 AC: 0 AN: 73924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00000564 AC: 6 AN: 1064056

Other (OTH) AF: 0.00 AC: 0 AN: 56842

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000567 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Nemaline myopathy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.78	T
PhyloP100		6.5
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.86	T
Sift4G	Uncertain	0.033	D
Vest4		0.63
MVP		0.64
MPC		0.14
ClinPred		0.50	D
GERP RS		6.0
gMVP		0.041
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs946188918; hg19: chr2-152355831;