2-151636277-C-T

Variant names:

• chr2-151636277-C-T
• rs192098032
• NM_001164507.2:c.9052G>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.9052G>A​(p.Asp3018Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000754 in 1,610,202 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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. D3018Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (14 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.54
• 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 (MetaRNN=0.010050595).
• BP6: Variant 2-151636277-C-T is Benign according to our data. Variant chr2-151636277-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00104 (158/152340) while in subpopulation EAS AF = 0.0256 (133/5194). AF 95% confidence interval is 0.0221. There are 3 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.9052G>A	p.Asp3018Asn	missense	Exon 64 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.9052G>A	p.Asp3018Asn	missense	Exon 64 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.9052G>A	p.Asp3018Asn	missense	Exon 64 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.9052G>A	p.Asp3018Asn	missense	Exon 64 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9052G>A	p.Asp3018Asn	missense	Exon 64 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.8853+3616G>A		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152222 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00255 AC: 629 AN: 246288 AF XY: 0.00236

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0342

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.000724 AC: 1056 AN: 1457862 Hom.: 14 Cov.: 31 AF XY: 0.000702 AC XY: 509 AN XY: 725338

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0217 AC: 862 AN: 39674

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49804

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111722

Other (OTH) AF: 0.00230 AC: 139 AN: 60336

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152340 Hom.: 3 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74500

African (AFR) AF: 0.000168 AC: 7 AN: 41574

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0256 AC: 133 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00122 Hom.: 3

Bravo AF: 0.00125

ExAC AF: 0.00222 AC: 268

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Nemaline myopathy 2 (1)
-	-	1	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.76	T
PhyloP100		7.5
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Vest4		0.72
MVP		0.53
MPC		0.34
ClinPred		0.062	T
GERP RS		6.0
gMVP		0.14
Mutation Taster		=65/35	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: rs192098032; hg19: chr2-152492791; COSMIC: COSV50837184;