rs150135749

Positions:

• chr2-151640397-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.8643C>T​(p.Ser2881=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,613,884 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 0.00096 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.00

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 2-151640397-G-A is Benign according to our data. Variant chr2-151640397-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 391111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000959 (146/152202) while in subpopulation AFR AF= 0.00315 (131/41546). AF 95% confidence interval is 0.00271. There are 1 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.8643C>T	p.Ser2881=	synonymous_variant	61/182	ENST00000427231.7
NEB	NM_001164508.2	c.8643C>T	p.Ser2881=	synonymous_variant	61/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.8643C>T	p.Ser2881=	synonymous_variant	61/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.8643C>T	p.Ser2881=	synonymous_variant	61/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8643C>T	p.Ser2881=	synonymous_variant	61/150	5

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.000962

GnomAD3 exomes AF: 0.000277 AC: 69 AN: 249122 Hom.: 0 AF XY: 0.000259 AC XY: 35 AN XY: 135148

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1461682 Hom.: 0 Cov.: 32 AF XY: 0.0000990 AC XY: 72 AN XY: 727124

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152202 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74406

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.000720

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: 0.000951

Alfa AF: 0.000514 Hom.: 0

Bravo AF: 0.00128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2019

- -

Nemaline myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.12
DANN	Benign	0.59

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: rs150135749; hg19: chr2-152496911;