rs1553872062

Variant names:

• chr2-151604717-T-A
• rs1553872062
• NM_001164507.2:c.12902A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164507.2(NEB):​c.12902A>T​(p.His4301Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.17
• Publications: 0 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15440813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.12902A>T	p.His4301Leu	missense_variant	Exon 85 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.12902A>T	p.His4301Leu	missense_variant	Exon 85 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.12902A>T	p.His4301Leu	missense_variant	Exon 85 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.12902A>T	p.His4301Leu	missense_variant	Exon 85 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11601+5092A>T		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 416354 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 219076

African (AFR) AF: 0.00 AC: 0 AN: 10778

American (AMR) AF: 0.00 AC: 0 AN: 16596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12764

East Asian (EAS) AF: 0.00 AC: 0 AN: 26692

South Asian (SAS) AF: 0.00 AC: 0 AN: 41926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1798

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 255984

Other (OTH) AF: 0.00 AC: 0 AN: 23946

GnomAD4 genome Cov.: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Jan 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.1
DANN	Benign	0.73
DEOGEN2	Benign	0.022	.;T;.;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.46	T;T;T;.;.
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PROVEAN	Benign	-1.0	N;.;N;.;.
REVEL	Benign	0.019
Sift	Benign	0.074	T;.;T;.;.
Sift4G	Benign	0.061	T;T;T;T;T
Vest4		0.35
MutPred		0.46		Loss of disorder (P = 0.0562);Loss of disorder (P = 0.0562);Loss of disorder (P = 0.0562);Loss of disorder (P = 0.0562);Loss of disorder (P = 0.0562);
MVP		0.35
MPC		0.28
ClinPred		0.15	T
GERP RS		0.13
gMVP		0.00064
Mutation Taster		=93/7	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: rs1553872062; hg19: chr2-152461231;