2-151706832-T-C

Variant names:

• chr2-151706832-T-C
• rs113401628
• NM_001164507.2:c.1152+49A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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=-0.83).
• BP6: Variant 2-151706832-T-C is Benign according to our data. Variant chr2-151706832-T-C is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.1152+49A>G		intron_variant	Intron 13 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.1152+49A>G		intron_variant	Intron 13 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.1152+49A>G		intron_variant	Intron 13 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.1152+49A>G		intron_variant	Intron 13 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000489048.1	n.51+49A>G		intron_variant	Intron 1 of 11	1
NEB	ENST00000409198.5	c.1152+49A>G		intron_variant	Intron 13 of 149	5		ENSP00000386259.1

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

GnomAD2 exomes AF: 0.0164 AC: 2460 AN: 150150 AF XY: 0.0174

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 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

African (AFR) AF: 0.00259 AC: 69 AN: 26662

American (AMR) AF: 0.00747 AC: 222 AN: 29738

Ashkenazi Jewish (ASJ) AF: 0.0479 AC: 1124 AN: 23474

East Asian (EAS) AF: 0.00 AC: 0 AN: 35810

South Asian (SAS) AF: 0.0271 AC: 1935 AN: 71502

European-Finnish (FIN) AF: 0.0121 AC: 602 AN: 49648

Middle Eastern (MID) AF: 0.0236 AC: 124 AN: 5256

European-Non Finnish (NFE) AF: 0.0166 AC: 14919 AN: 899600

Other (OTH) AF: 0.0192 AC: 981 AN: 51118

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

African (AFR) AF: 0.00286 AC: 119 AN: 41574

American (AMR) AF: 0.0107 AC: 164 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4832

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1173 AN: 68024

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

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

-

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

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: rs113401628; hg19: chr2-152563346;