chr2-151579592-C-T

Position:

• chr2-151579592-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164508.2(NEB):​c.16450G>A​(p.Ala5484Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (242 hom., cov: 9)
  • Exomes 𝑓: 0.065 (4599 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.961

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015130043).
• BP6: Variant 2-151579592-C-T is Benign according to our data. Variant chr2-151579592-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151579592-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16450G>A	p.Ala5484Thr	missense_variant	105/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16450G>A	p.Ala5484Thr	missense_variant	105/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16450G>A	p.Ala5484Thr	missense_variant	105/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.16450G>A	p.Ala5484Thr	missense_variant	105/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000413693.5	c.640G>A	p.Ala214Thr	missense_variant	5/74	5		ENSP00000410961.1
NEB	ENST00000409198.5	c.11602-3238G>A		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4279 AN: 64334 Hom.: 242 Cov.: 9 FAILED QC

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0556

Gnomad NFE AF: 0.0782

Gnomad OTH AF: 0.0657

GnomAD3 exomes AF: 0.0665 AC: 2624 AN: 39442 Hom.: 489 AF XY: 0.0650 AC XY: 1301 AN XY: 20006

Gnomad AFR exome AF: 0.0604

Gnomad AMR exome AF: 0.0622

Gnomad ASJ exome AF: 0.0850

Gnomad EAS exome AF: 0.0222

Gnomad SAS exome AF: 0.0561

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.0765

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0648 AC: 71144 AN: 1098712 Hom.: 4599 Cov.: 16 AF XY: 0.0635 AC XY: 35035 AN XY: 551350

Gnomad4 AFR exome AF: 0.0530

Gnomad4 AMR exome AF: 0.0325

Gnomad4 ASJ exome AF: 0.0758

Gnomad4 EAS exome AF: 0.0305

Gnomad4 SAS exome AF: 0.0430

Gnomad4 FIN exome AF: 0.0801

Gnomad4 NFE exome AF: 0.0692

Gnomad4 OTH exome AF: 0.0601

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0665 AC: 4285 AN: 64458 Hom.: 242 Cov.: 9 AF XY: 0.0660 AC XY: 1954 AN XY: 29602

Gnomad4 AFR AF: 0.0526

Gnomad4 AMR AF: 0.0612

Gnomad4 ASJ AF: 0.0925

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.0402

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0782

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0565 Hom.: 83

ExAC AF: 0.0599 AC: 186

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nemaline myopathy 2 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.012	.;T;.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D;.;.
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.55	N;.;N;N;.;.
REVEL	Benign	0.036
Sift	Benign	0.036	D;.;D;D;.;.
Sift4G	Uncertain	0.027	D;D;D;D;D;D
Vest4		0.14
MPC		0.34
ClinPred		0.012	T
GERP RS		4.7
gMVP		0.0016

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs536508687; hg19: chr2-152436106; COSMIC: COSV50816930;