rs532130242

Variant names:

• chr2-151679728-G-A
• rs532130242
• NM_001164507.2:c.3248C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PP3_Moderate BP6_Moderate BS2_Supporting

The NM_001164507.2(NEB):​c.3248C>T​(p.Ala1083Val) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,378,874 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A1083A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000088 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00013 (3 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.61
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-151679728-G-A is Benign according to our data. Variant chr2-151679728-G-A is described in ClinVar as Benign. ClinVar VariationId is 465599.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.3248C>T	p.Ala1083Val	missense	Exon 32 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.3248C>T	p.Ala1083Val	missense	Exon 32 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.3248C>T	p.Ala1083Val	missense	Exon 32 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.3248C>T	p.Ala1083Val	missense	Exon 32 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.3248C>T	p.Ala1083Val	missense	Exon 32 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.3248C>T	p.Ala1083Val	missense	Exon 32 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0000878 AC: 12 AN: 136750 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00287

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000233 AC: 58 AN: 248438 AF XY: 0.000260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 162 AN: 1242008 Hom.: 3 Cov.: 32 AF XY: 0.000159 AC XY: 98 AN XY: 615598

African (AFR) AF: 0.000111 AC: 3 AN: 26926

American (AMR) AF: 0.0000263 AC: 1 AN: 38052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17874

East Asian (EAS) AF: 0.0000499 AC: 1 AN: 20060

South Asian (SAS) AF: 0.00163 AC: 137 AN: 84114

European-Finnish (FIN) AF: 0.0000285 AC: 1 AN: 35120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4602

European-Non Finnish (NFE) AF: 0.0000134 AC: 13 AN: 969624

Other (OTH) AF: 0.000131 AC: 6 AN: 45636

GnomAD4 genome AF: 0.0000877 AC: 12 AN: 136866 Hom.: 0 Cov.: 30 AF XY: 0.000152 AC XY: 10 AN XY: 65836

African (AFR) AF: 0.0000271 AC: 1 AN: 36940

American (AMR) AF: 0.00 AC: 0 AN: 13054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3348

East Asian (EAS) AF: 0.00 AC: 0 AN: 3992

South Asian (SAS) AF: 0.00286 AC: 11 AN: 3846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64756

Other (OTH) AF: 0.00 AC: 0 AN: 1950

Alfa AF: 0.0000219 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000207 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Benign	0.064
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		0.85	P
Vest4		0.53
MutPred		0.52		Loss of disorder (P = 0.0744)
MVP		0.54
MPC		0.15
ClinPred		0.062	T
GERP RS		5.7
Varity_R		0.16
gMVP		0.36
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs532130242; hg19: chr2-152536242; COSMIC: COSV51436034;