chr2-151610487-C-T

Variant names:

• chr2-151610487-C-T
• rs11902616
• NM_001164507.2:c.12018+29G>A

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.12018+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,540,414 control chromosomes in the GnomAD database, including 6,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2289 hom., cov: 32)
  • Exomes 𝑓: 0.039 (3809 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.494
• Publications: 4 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=-0.75).
• BP6: Variant 2-151610487-C-T is Benign according to our data. Variant chr2-151610487-C-T is described in ClinVar as Benign. ClinVar VariationId is 257726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.12018+29G>A		intron_variant	Intron 80 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.12018+29G>A		intron_variant	Intron 80 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.12018+29G>A		intron_variant	Intron 80 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.12018+29G>A		intron_variant	Intron 80 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11289+29G>A		intron_variant	Intron 77 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17374 AN: 151940 Hom.: 2268 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0572

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0994

GnomAD2 exomes AF: 0.0659 AC: 16298 AN: 247142 AF XY: 0.0654

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0393 AC: 54577 AN: 1388356 Hom.: 3809 Cov.: 26 AF XY: 0.0414 AC XY: 28766 AN XY: 694708

African (AFR) AF: 0.339 AC: 10784 AN: 31786

American (AMR) AF: 0.0282 AC: 1257 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 1637 AN: 25600

East Asian (EAS) AF: 0.168 AC: 6592 AN: 39294

South Asian (SAS) AF: 0.133 AC: 11208 AN: 84498

European-Finnish (FIN) AF: 0.0148 AC: 791 AN: 53302

Middle Eastern (MID) AF: 0.0514 AC: 288 AN: 5598

European-Non Finnish (NFE) AF: 0.0177 AC: 18465 AN: 1045862

Other (OTH) AF: 0.0614 AC: 3555 AN: 57880

GnomAD4 genome AF: 0.115 AC: 17460 AN: 152058 Hom.: 2289 Cov.: 32 AF XY: 0.114 AC XY: 8491 AN XY: 74352

African (AFR) AF: 0.316 AC: 13077 AN: 41414

American (AMR) AF: 0.0571 AC: 872 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3468

East Asian (EAS) AF: 0.167 AC: 863 AN: 5172

South Asian (SAS) AF: 0.146 AC: 705 AN: 4826

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10602

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1247 AN: 67986

Other (OTH) AF: 0.110 AC: 232 AN: 2114

Alfa AF: 0.0511 Hom.: 863

Bravo AF: 0.126

Asia WGS AF: 0.215 AC: 745 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	-0.75
CADD	Benign	5.3
DANN	Benign	0.73
PhyloP100		-0.49
Mutation Taster		=99/1	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: rs11902616; hg19: chr2-152467001; COSMIC: COSV50807631;