rs753691207

Positions:

• chr2-151680785-A-G
• chr2-151680785-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_001164507.2(NEB):​c.2987T>C​(p.Ile996Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I996N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 6.45

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• BP6: Variant 2-151680785-A-G is Benign according to our data. Variant chr2-151680785-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 565923.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.2987T>C	p.Ile996Thr	missense_variant	30/182	ENST00000427231.7
NEB	NM_001164508.2	c.2987T>C	p.Ile996Thr	missense_variant	30/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.2987T>C	p.Ile996Thr	missense_variant	30/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.2987T>C	p.Ile996Thr	missense_variant	30/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.2987T>C	p.Ile996Thr	missense_variant	30/150	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249188 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135186

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461244 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;.
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M;M;.;M;M;M;M
MutationTaster	Benign	0.86	N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N;N;.;N;N;.;.
REVEL	Benign	0.26
Sift	Benign	0.032	D;T;.;T;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.94	.;.;.;.;P;.;.
Vest4		0.78
MutPred		0.76		Gain of disorder (P = 0.0235);Gain of disorder (P = 0.0235);Gain of disorder (P = 0.0235);Gain of disorder (P = 0.0235);Gain of disorder (P = 0.0235);Gain of disorder (P = 0.0235);Gain of disorder (P = 0.0235);
MVP		0.56
MPC		0.36
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.13
gMVP		0.25

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: rs753691207; hg19: chr2-152537299;