2-151631294-A-T

Variant names:

• chr2-151631294-A-T
• rs145770770
• NM_001164507.2:c.9467T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.9467T>A​(p.Ile3156Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,613,792 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3156F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 32)
  • Exomes 𝑓: 0.017 (250 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.46
• Publications: 9 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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 (MetaRNN=0.0072318614).
• BP6: Variant 2-151631294-A-T is Benign according to our data. Variant chr2-151631294-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1537/152178) while in subpopulation NFE AF = 0.0176 (1197/67994). AF 95% confidence interval is 0.0168. There are 11 homozygotes in GnomAd4. There are 688 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.9467T>A	p.Ile3156Asn	missense	Exon 66 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.9467T>A	p.Ile3156Asn	missense	Exon 66 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.9467T>A	p.Ile3156Asn	missense	Exon 66 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.9467T>A	p.Ile3156Asn	missense	Exon 66 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9467T>A	p.Ile3156Asn	missense	Exon 66 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.8854-116T>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152060 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.0109 AC: 2716 AN: 249044 AF XY: 0.0119

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.0166 AC: 24214 AN: 1461614 Hom.: 250 Cov.: 31 AF XY: 0.0165 AC XY: 12024 AN XY: 727078

African (AFR) AF: 0.00269 AC: 90 AN: 33478

American (AMR) AF: 0.00219 AC: 98 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39690

South Asian (SAS) AF: 0.0213 AC: 1840 AN: 86256

European-Finnish (FIN) AF: 0.00579 AC: 309 AN: 53382

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0189 AC: 20987 AN: 1111810

Other (OTH) AF: 0.0141 AC: 852 AN: 60372

GnomAD4 genome AF: 0.0101 AC: 1537 AN: 152178 Hom.: 11 Cov.: 32 AF XY: 0.00924 AC XY: 688 AN XY: 74422

African (AFR) AF: 0.00344 AC: 143 AN: 41538

American (AMR) AF: 0.00367 AC: 56 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4818

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1197 AN: 67994

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00458 Hom.: 2

Bravo AF: 0.00926

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.0167 AC: 53

ExAC AF: 0.0110 AC: 1325

EpiCase AF: 0.0150

EpiControl AF: 0.0137

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Nemaline myopathy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.061
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.2	T
PhyloP100		1.5
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Benign	0.037	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.32
MPC		0.41
ClinPred		0.041	T
GERP RS		5.9
gMVP		0.057
Mutation Taster		=64/36	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: rs145770770; hg19: chr2-152487808; COSMIC: COSV106082349;