rs34504204

Variant names:

• chr2-151565084-T-A
• rs34504204
• NM_001164507.2:c.18431A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151565084-T-A
• chr2-151565084-T-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_001164507.2(NEB):​c.18431A>T​(p.His6144Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,447,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. H6144R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.71
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11429396).
• BP6: Variant 2-151565084-T-A is Benign according to our data. Variant chr2-151565084-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1378589.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.18431A>T	p.His6144Leu	missense_variant	Exon 117 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18431A>T	p.His6144Leu	missense_variant	Exon 117 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.18431A>T	p.His6144Leu	missense_variant	Exon 117 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.18431A>T	p.His6144Leu	missense_variant	Exon 117 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000244 AC: 6 AN: 246206 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1447142 Hom.: 0 Cov.: 28 AF XY: 0.00000555 AC XY: 4 AN XY: 720368

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 84986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000727 AC: 8 AN: 1100286

Other (OTH) AF: 0.0000501 AC: 3 AN: 59834

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Benign:1

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.073	.;.;T;.;T;T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T;T;T;T;T;T;.;.
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.;N;.;.;.
PhyloP100		1.7
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N;N;.;D;N;D;.;.
REVEL	Benign	0.14
Sift	Benign	0.54	T;D;.;D;T;D;.;.
Sift4G	Benign	0.080	T;T;T;T;T;T;T;T
Polyphen		0.0030	.;.;.;.;B;.;.;.
Vest4		0.21
MutPred		0.49		Gain of stability (P = 0.0144);.;.;.;Gain of stability (P = 0.0144);.;.;.;
MVP		0.53
MPC		0.074
ClinPred		0.14	T
GERP RS		6.0
Varity_R		0.16
gMVP		0.41
Mutation Taster		=91/9	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: rs34504204; hg19: chr2-152421598;