2-151706832-T-C

Position:

• chr2-151706832-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.1152+49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,345,140 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 32)
  • Exomes 𝑓: 0.017 (225 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.370

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151706832-T-C is Benign according to our data. Variant chr2-151706832-T-C is described in ClinVar as [Benign]. Clinvar id is 257723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0124 (1894/152332) while in subpopulation SAS AF= 0.0209 (101/4832). AF 95% confidence interval is 0.0176. There are 21 homozygotes in gnomad4. There are 918 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.1152+49A>G		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.1152+49A>G		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.1152+49A>G		intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.1152+49A>G		intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000489048.1	n.51+49A>G		intron_variant, non_coding_transcript_variant		1
NEB	ENST00000409198.5	c.1152+49A>G		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152214 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0164 AC: 2460 AN: 150150 Hom.: 31 AF XY: 0.0174 AC XY: 1364 AN XY: 78530

Gnomad AFR exome AF: 0.00249

Gnomad AMR exome AF: 0.00724

Gnomad ASJ exome AF: 0.0483

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0271

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0167 AC: 19976 AN: 1192808 Hom.: 225 Cov.: 16 AF XY: 0.0172 AC XY: 10299 AN XY: 597778

Gnomad4 AFR exome AF: 0.00259

Gnomad4 AMR exome AF: 0.00747

Gnomad4 ASJ exome AF: 0.0479

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0271

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0124 AC: 1894 AN: 152332 Hom.: 21 Cov.: 32 AF XY: 0.0123 AC XY: 918 AN XY: 74492

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0188 Hom.: 6

Bravo AF: 0.0113

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.73

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: rs113401628; hg19: chr2-152563346;