chr2-151540756-C-A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001164507.2(NEB):c.20728G>T(p.Ala6910Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A6910T) has been classified as Likely benign.
Frequency
Consequence
NM_001164507.2 missense
Scores
Clinical Significance
Conservation
Publications
- nemaline myopathy 2Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
- childhood-onset nemaline myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- intermediate nemaline myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- typical nemaline myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- lethal multiple pterygium syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- severe congenital nemaline myopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.20728G>T | p.Ala6910Ser | missense_variant | Exon 137 of 182 | 5 | NM_001164508.2 | ENSP00000380505.3 | ||
NEB | ENST00000427231.7 | c.20728G>T | p.Ala6910Ser | missense_variant | Exon 137 of 182 | 5 | NM_001164507.2 | ENSP00000416578.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.0000161 AC: 4AN: 248764 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461342Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726954 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.15625G>T (p.A5209S) alteration is located in exon 110 (coding exon 108) of the NEB gene. This alteration results from a G to T substitution at nucleotide position 15625, causing the alanine (A) at amino acid position 5209 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Nemaline myopathy 2 Uncertain:1
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. 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: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is present in population databases (rs750152377, gnomAD 0.004%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6910 of the NEB protein (p.Ala6910Ser). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at