rs199862790
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBS1_SupportingBS2_Supporting
The NM_001164508.2(NEB):āc.6020T>Cā(p.Met2007Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,613,226 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001164508.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.6020T>C | p.Met2007Thr | missense_variant | Exon 47 of 182 | 5 | NM_001164508.2 | ENSP00000380505.3 | ||
NEB | ENST00000427231.7 | c.6020T>C | p.Met2007Thr | missense_variant | Exon 47 of 182 | 5 | NM_001164507.2 | ENSP00000416578.2 | ||
NEB | ENST00000409198.5 | c.6020T>C | p.Met2007Thr | missense_variant | Exon 47 of 150 | 5 | ENSP00000386259.1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000390 AC: 97AN: 248948Hom.: 0 AF XY: 0.000585 AC XY: 79AN XY: 135046
GnomAD4 exome AF: 0.000227 AC: 332AN: 1460926Hom.: 2 Cov.: 30 AF XY: 0.000326 AC XY: 237AN XY: 726780
GnomAD4 genome AF: 0.000138 AC: 21AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74472
ClinVar
Submissions by phenotype
Nemaline myopathy 2 Uncertain:3Benign:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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Inborn genetic diseases Uncertain:1
The c.6020T>C (p.M2007T) alteration is located in exon 47 (coding exon 45) of the NEB gene. This alteration results from a T to C substitution at nucleotide position 6020, causing the methionine (M) at amino acid position 2007 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
NEB-related disorder Uncertain:1
The NEB c.6020T>C variant is predicted to result in the amino acid substitution p.Met2007Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.32% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152515634-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at