rs368315910

Variant names:

• chr2-151529256-G-A
• rs368315910
• NM_001164507.2:c.21689C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_001164507.2(NEB):​c.21689C>T​(p.Ala7230Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 7.99
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29810974).
• BP6: Variant 2-151529256-G-A is Benign according to our data. Variant chr2-151529256-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 565717.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.21689C>T	p.Ala7230Val	missense_variant	Exon 146 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.21689C>T	p.Ala7230Val	missense_variant	Exon 146 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.21689C>T	p.Ala7230Val	missense_variant	Exon 146 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.21689C>T	p.Ala7230Val	missense_variant	Exon 146 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249122 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461392 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111598

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000414 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	.;.;T;.;T;T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;T;D;D;D;.;.
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.;.;L;.;.;.
PhyloP100		8.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N;N;.;N;N;N;.;.
REVEL	Benign	0.099
Sift	Benign	0.038	D;T;.;T;D;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		0.57	.;.;.;.;P;.;.;.
Vest4		0.47
MVP		0.45
MPC		0.29
ClinPred		0.36	T
GERP RS		5.8
Varity_R		0.25
gMVP		0.53
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs368315910; hg19: chr2-152385770;