2-151666042-T-C

Variant names:

• chr2-151666042-T-C
• rs4664496
• NM_001164507.2:c.5031+48A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.5031+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,544,304 control chromosomes in the GnomAD database, including 22,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3947 hom., cov: 32)
  • Exomes 𝑓: 0.14 (18486 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.310
• Publications: 3 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-151666042-T-C is Benign according to our data. Variant chr2-151666042-T-C is described in ClinVar as Benign. ClinVar VariationId is 257816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.5031+48A>G		intron_variant	Intron 41 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.5031+48A>G		intron_variant	Intron 41 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.5031+48A>G		intron_variant	Intron 41 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.5031+48A>G		intron_variant	Intron 41 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.5031+48A>G		intron_variant	Intron 41 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29308 AN: 151988 Hom.: 3925 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.177 AC: 37585 AN: 212230 AF XY: 0.177

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.481

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.136 AC: 188644 AN: 1392198 Hom.: 18486 Cov.: 29 AF XY: 0.139 AC XY: 95102 AN XY: 686184

African (AFR) AF: 0.357 AC: 11371 AN: 31894

American (AMR) AF: 0.104 AC: 4258 AN: 40982

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3517 AN: 22556

East Asian (EAS) AF: 0.514 AC: 20077 AN: 39052

South Asian (SAS) AF: 0.281 AC: 21404 AN: 76088

European-Finnish (FIN) AF: 0.125 AC: 6375 AN: 50820

Middle Eastern (MID) AF: 0.139 AC: 582 AN: 4174

European-Non Finnish (NFE) AF: 0.104 AC: 111718 AN: 1069260

Other (OTH) AF: 0.163 AC: 9342 AN: 57372

GnomAD4 genome AF: 0.193 AC: 29378 AN: 152106 Hom.: 3947 Cov.: 32 AF XY: 0.195 AC XY: 14482 AN XY: 74362

African (AFR) AF: 0.341 AC: 14130 AN: 41448

American (AMR) AF: 0.120 AC: 1837 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 536 AN: 3472

East Asian (EAS) AF: 0.493 AC: 2553 AN: 5176

South Asian (SAS) AF: 0.283 AC: 1360 AN: 4808

European-Finnish (FIN) AF: 0.118 AC: 1255 AN: 10602

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7143 AN: 67996

Other (OTH) AF: 0.187 AC: 394 AN: 2110

Alfa AF: 0.147 Hom.: 446

Bravo AF: 0.199

Asia WGS AF: 0.414 AC: 1434 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	-0.91
CADD	Benign	9.5
DANN	Benign	0.71
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4664496; hg19: chr2-152522556; COSMIC: COSV50874219; COSMIC: COSV50874219;