rs199937246

Positions:

• chr2-151494220-C-G
• chr2-151494220-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164508.2(NEB):​c.24520G>C​(p.Ala8174Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.65

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:):

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.24520G>C	p.Ala8174Pro	missense_variant	174/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.24520G>C	p.Ala8174Pro	missense_variant	174/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.24520G>C	p.Ala8174Pro	missense_variant	174/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.24520G>C	p.Ala8174Pro	missense_variant	174/182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453230 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0077	.;.;T;.;T;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.042	T;T;T;T;T;T;.;.
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.3	N;N;.;N;N;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.56	T;T;.;T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.;.
Vest4		0.33
MutPred		0.65		Gain of glycosylation at A6318 (P = 0.0532);.;.;.;Gain of glycosylation at A6318 (P = 0.0532);.;.;.;
MVP		0.24
MPC		0.063
ClinPred		0.71	D
GERP RS		5.1
Varity_R		0.099
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 33

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-152350734;