rs187211085

chr2-151554982-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001164507.2(NEB):c.19377C>T(p.Asp6459=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.68

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-151554982-G-A is Benign according to our data. Variant chr2-151554982-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00139 (212/152232) while in subpopulation AFR AF= 0.00494 (205/41526). AF 95% confidence interval is 0.00438. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.19377C>T	p.Asp6459=	synonymous_variant	125/182	ENST00000427231.7
NEB	NM_001164508.2	c.19377C>T	p.Asp6459=	synonymous_variant	125/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.19377C>T	p.Asp6459=	synonymous_variant	125/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.19377C>T	p.Asp6459=	synonymous_variant	125/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000401 AC: 100 AN: 249090 Hom.: 0 AF XY: 0.000407 AC XY: 55 AN XY: 135126

Gnomad AFR exome AF: 0.00497

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 255 AN: 1461540 Hom.: 1 Cov.: 31 AF XY: 0.000166 AC XY: 121 AN XY: 727068

Gnomad4 AFR exome AF: 0.00520

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74452

Gnomad4 AFR AF: 0.00494

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000867 Hom.: 0

Bravo AF: 0.00147

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 18, 2019	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.21
Dann	Benign	0.75

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: rs187211085; hg19: chr2-152411496; COSMIC: COSV51423812;