2-151619424-T-G

Variant names:

• chr2-151619424-T-G
• rs10186656
• NM_001164507.2:c.10872+27A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.10872+27A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,558,888 control chromosomes in the GnomAD database, including 107,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7955 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99771 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.322

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=-0.89).
• BP6: Variant 2-151619424-T-G is Benign according to our data. Variant chr2-151619424-T-G is described in ClinVar as [Benign]. Clinvar id is 257720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151619424-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.10872+27A>C		intron_variant	Intron 73 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.10872+27A>C		intron_variant	Intron 73 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.10872+27A>C		intron_variant	Intron 73 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.10872+27A>C		intron_variant	Intron 73 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.10143+27A>C		intron_variant	Intron 70 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47312 AN: 151992 Hom.: 7951 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.314

GnomAD3 exomes AF: 0.337 AC: 73263 AN: 217256 Hom.: 13001 AF XY: 0.336 AC XY: 38900 AN XY: 115712

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.351

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.264

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.371 AC: 522277 AN: 1406778 Hom.: 99771 Cov.: 31 AF XY: 0.368 AC XY: 254321 AN XY: 691998

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.346

GnomAD4 genome AF: 0.311 AC: 47334 AN: 152110 Hom.: 7955 Cov.: 32 AF XY: 0.310 AC XY: 23047 AN XY: 74356

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.247

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.402

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.311

Alfa AF: 0.239 Hom.: 1018

Bravo AF: 0.300

Asia WGS AF: 0.244 AC: 849 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nemaline myopathy 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.088
DANN	Benign	0.31

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: rs10186656; hg19: chr2-152475938; COSMIC: COSV50807001; COSMIC: COSV50807001;