NM_001164507.2:c.22642A>G

Variant names:

• chr2-151519018-T-C
• rs201976154
• NM_001164507.2:c.22642A>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001164507.2(NEB):​c.22642A>G​(p.Lys7548Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.75

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10933238).
• BP6: Variant 2-151519018-T-C is Benign according to our data. Variant chr2-151519018-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465567.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.22642A>G	p.Lys7548Glu	missense_variant	Exon 155 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.22642A>G	p.Lys7548Glu	missense_variant	Exon 155 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.22642A>G	p.Lys7548Glu	missense_variant	Exon 155 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.22642A>G	p.Lys7548Glu	missense_variant	Exon 155 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 248974 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 135054

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1461428 Hom.: 0 Cov.: 30 AF XY: 0.000176 AC XY: 128 AN XY: 726992

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74376

Gnomad4 AFR AF: 0.0000483

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: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.000873

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2 Benign:1

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEB-related disorder Uncertain:1

Jan 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NEB c.22747A>G variant is predicted to result in the amino acid substitution p.Lys7583Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Mar 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	.;.;T;.;T;T;.;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D;D;T;D;D;D;.;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.090	N;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;N;.;N;N;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.64	T;T;.;T;T;T;.;.
Sift4G	Benign	0.085	T;T;T;T;T;T;T;T
Polyphen		0.21	.;.;.;.;B;.;.;.
Vest4		0.43
MVP		0.43
MPC		0.29
ClinPred		0.050	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs201976154; hg19: chr2-152375532;