rs200125713

Positions:

• chr2-151600602-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.13628A>C​(p.Lys4543Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 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. K4543K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.17 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.551

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024766624).
• BP6: Variant 2-151600602-T-G is Benign according to our data. Variant chr2-151600602-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 226842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151600602-T-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.13628A>C	p.Lys4543Thr	missense_variant	89/182	ENST00000427231.7
NEB	NM_001164508.2	c.13628A>C	p.Lys4543Thr	missense_variant	89/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.13628A>C	p.Lys4543Thr	missense_variant	89/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.13628A>C	p.Lys4543Thr	missense_variant	89/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+9207A>C		intron_variant		5

Frequencies

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

GnomAD3 exomes AF: 0.204 AC: 2030 AN: 9974 Hom.: 1 AF XY: 0.195 AC XY: 1086 AN XY: 5572

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.165 AC: 2415 AN: 14614 Hom.: 1 Cov.: 0 AF XY: 0.164 AC XY: 1330 AN XY: 8092

Gnomad4 AFR exome AF: 0.0786

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.161

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: 0.0525 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 09, 2015	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 82, 90, and 98) are co-amplified and sequenced (each amplicon consists of 6 a lleles). Due to this method, we are unable to determine in which repetitive bloc k this variant occurs [c.13628A>C (p.Lys4543Thr) in exon 89; c.15086A>C (pLys502 9Thr) in exon 97; c.16544A>C (p.Lys5515Thr) in exon 105]. This variant is not ex pected to have clinical significance because it has been identified in 34.4% (10 44/3038) chromosomes across several diverse populations by the Exome Aggregate C onsortium (http://exac.broadinstitute.org/variant/2-152436012-T-G). -

Nemaline myopathy 2 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.1
DANN	Benign	0.33
DEOGEN2	Benign	0.018	.;T;.;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.71	T;T;T;.;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.40	N;.;N;.;.
REVEL	Benign	0.076
Sift	Benign	0.030	D;.;D;.;.
Sift4G	Benign	0.063	T;T;T;T;T
Vest4		0.18
MutPred		0.51		Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);
MPC		0.22
ClinPred		0.017	T
GERP RS		-3.3
gMVP		0.0034

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: rs200125713; hg19: chr2-152457116;