rs200624735

Positions:

• chr2-151640487-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001164507.2(NEB):​c.8553G>A​(p.Gly2851=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,862 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -4.48

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-151640487-C-T is Benign according to our data. Variant chr2-151640487-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281363.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-4.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000927 (141/152154) while in subpopulation AFR AF= 0.00294 (122/41498). AF 95% confidence interval is 0.00252. There are 2 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.8553G>A	p.Gly2851=	synonymous_variant	61/182	ENST00000427231.7
NEB	NM_001164508.2	c.8553G>A	p.Gly2851=	synonymous_variant	61/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.8553G>A	p.Gly2851=	synonymous_variant	61/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.8553G>A	p.Gly2851=	synonymous_variant	61/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8553G>A	p.Gly2851=	synonymous_variant	61/150	5

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

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: 0.00192

GnomAD3 exomes AF: 0.000217 AC: 54 AN: 249248 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135214

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65 AN XY: 727136

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.000201

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: 0.0000306

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000927 AC: 141 AN: 152154 Hom.: 2 Cov.: 32 AF XY: 0.000901 AC XY: 67 AN XY: 74390

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.000850

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: 0.00190

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000990

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 10, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.64
DANN	Benign	0.55

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: rs200624735; hg19: chr2-152497001;