rs201352230
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_006506.5(RASA2):c.17C>T(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,392,716 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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_006506.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RASA2 | NM_006506.5 | c.17C>T | p.Pro6Leu | missense_variant | Exon 1 of 24 | ENST00000286364.9 | NP_006497.2 | |
RASA2 | NM_001303246.3 | c.17C>T | p.Pro6Leu | missense_variant | Exon 1 of 25 | NP_001290175.1 | ||
RASA2 | NM_001303245.3 | c.17C>T | p.Pro6Leu | missense_variant | Exon 1 of 24 | NP_001290174.1 | ||
RASA2 | XM_047448652.1 | c.17C>T | p.Pro6Leu | missense_variant | Exon 1 of 17 | XP_047304608.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RASA2 | ENST00000286364.9 | c.17C>T | p.Pro6Leu | missense_variant | Exon 1 of 24 | 1 | NM_006506.5 | ENSP00000286364.3 | ||
RASA2 | ENST00000515549.1 | n.17C>T | non_coding_transcript_exon_variant | Exon 1 of 5 | 4 | ENSP00000424293.1 |
Frequencies
GnomAD3 genomes AF: 0.00338 AC: 509AN: 150574Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00357 AC: 281AN: 78770Hom.: 2 AF XY: 0.00317 AC XY: 141AN XY: 44512
GnomAD4 exome AF: 0.00545 AC: 6773AN: 1242034Hom.: 25 Cov.: 31 AF XY: 0.00532 AC XY: 3252AN XY: 611394
GnomAD4 genome AF: 0.00337 AC: 508AN: 150682Hom.: 1 Cov.: 32 AF XY: 0.00293 AC XY: 216AN XY: 73610
ClinVar
Submissions by phenotype
not provided Benign:4
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RASA2: BS1, BS2 -
not specified Uncertain:1Benign:2
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Variant summary: RASA2 c.17C>T (p.Pro6Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 78770 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 713 fold of the estimated maximal expected allele frequency for a pathogenic variant in RASA2 causing Noonan Syndrome and Related Conditions phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.17C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
RASA2-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at