chr2-151600509-T-C

Position:

• chr2-151600509-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.13721A>G​(p.His4574Arg) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H4574H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.11

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2096799).
• BP6: Variant 2-151600509-T-C is Benign according to our data. Variant chr2-151600509-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151600509-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.13721A>G	p.His4574Arg	missense_variant	89/182	ENST00000427231.7
NEB	NM_001164508.2	c.13721A>G	p.His4574Arg	missense_variant	89/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.13721A>G	p.His4574Arg	missense_variant	89/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.13721A>G	p.His4574Arg	missense_variant	89/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+9300A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 0 Hom.: 0 Cov.: 0 FAILED QC

GnomAD4 exome AF: 0.0709 AC: 96 AN: 1354 Hom.: 0 Cov.: 0 AF XY: 0.0595 AC XY: 42 AN XY: 706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0867

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0622

Gnomad4 OTH exome AF: 0.0714

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 0

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.409 Hom.: 39

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2014	NEB exons 82-105 are organized in three repetitive blocks of 8 exons each and be cause these blocks are nearly identical in sequence, homologous exons (e.g., exo ns 89, 97, and 105) are co-amplified and sequenced (each amplicon consists of 6 alleles). This variant represents a nonhomologous position within the three repe titive blocks (c.13721A, c.15179A, and c.16637G) and is categorized as "Likely B enign" (even though it does not meet LMM criteria) to prevent Sanger follow-up o f this nonhomologous position. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Nemaline myopathy 2 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.45
DEOGEN2	Benign	0.010	.;T;.;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;T;T;.;.
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	0.080	N;.;N;.;.
REVEL	Benign	0.057
Sift	Benign	0.099	T;.;T;.;.
Sift4G	Uncertain	0.037	D;D;D;D;D
Vest4		0.15
MutPred		0.45		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MPC		0.15
ClinPred		0.016	T
GERP RS		2.5
gMVP		0.0016

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657542; hg19: chr2-152457023;