rs753996512
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001164507.2(NEB):c.8162G>A(p.Arg2721His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,601,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2721C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001164507.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.8162G>A | p.Arg2721His | missense_variant, splice_region_variant | 59/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.8162G>A | p.Arg2721His | missense_variant, splice_region_variant | 59/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.8162G>A | p.Arg2721His | missense_variant, splice_region_variant | 59/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.8162G>A | p.Arg2721His | missense_variant, splice_region_variant | 59/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.8162G>A | p.Arg2721His | missense_variant, splice_region_variant | 59/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000853 AC: 2AN: 234552Hom.: 0 AF XY: 0.00000788 AC XY: 1AN XY: 126850
GnomAD4 exome AF: 0.0000124 AC: 18AN: 1449592Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8AN XY: 720658
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74270
ClinVar
Submissions by phenotype
Nemaline myopathy 2 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2721 of the NEB protein (p.Arg2721His). This variant is present in population databases (rs753996512, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 465644). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at