rs727504571
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
This summary comes from the ClinGen Evidence Repository: The c.622A>G (p.Ile208Val) variant in BRAF is present in 0.00001% (2/128934) European alleles in gnomAD. The computational predictor REVEL gives a score of 0.318, which is neither above nor below the thresholds predicting a damaging or benign impact on BRAF function. This variant was observed in two healthy adult individuals who did not have clinical features of a RASopathy (SCV000205449.5; PMID:29945942). Additionally, 12 apparently unaffected parental samples were observed with this variant (BS2; SCV000329576.8, SCV001011557.1). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS2, PP2 (RASopathy VCEP specifications version 1; 8/11/22). LINK:https://erepo.genome.network/evrepo/ui/classification/CA183392/MONDO:0021060/004
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.622A>G | p.Ile208Val | missense_variant | 5/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.622A>G | p.Ile208Val | missense_variant | 5/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.622A>G | p.Ile208Val | missense_variant | 5/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.622A>G | p.Ile208Val | missense_variant | 5/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251166Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135752
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1460448Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 726608
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74280
ClinVar
Submissions by phenotype
RASopathy Uncertain:1Benign:1
Uncertain significance, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Mar 09, 2020 | The c.622A>G (p.Ile208Val) variant in BRAF is present in 0.00001% (2/128934) European alleles in gnomAD. This variant was observed in two healthy adult individuals who did not have clinical features of a RASopathy (SCV000205449.5; PMID:29945942). Additionally, 12 apparently unaffected parental samples were observed with this variant, however this evidence does not meet current scoring criteria for BS2 at this time (BS2 not met; SCV000329576.8, SCV001011557.1). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Ile208Val variant is uncertain at this time. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jul 01, 2022 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 21, 2018 | We observed the Ile208Val variant in BRAF in one individual with middle aortic s yndrome, low nasal bridge, hypertension, facial coarseness, short stature, learn ing disabilities/mental retardation, wide-spaced nipples and webbed neck and her reportedly unaffected parent, both tested by our laboratory. The variant was al so found in a fetus with increased nuchal translucency and her unaffected father (personal communication with the mother via our ClinVar entry). GeneDx observed the variant in three unrelated families undergoing exome testing in which the c linical presentations of individuals with the variant (n=6) were either normal o r had clinical features inconsistent with a RASopathy. This variant has also bee n found in the general population at a frequency of 3/276842 alleles (gnomAD, rs 727504571). Ile208Val has been reported in a melanoma cell line which also carri ed Val600Glu, a well-characterized activating mutation (Ikediobi 2006). Computat ional analyses (biochemical amino acid properties, conservation, AlignGVGD, Poly Phen2, and SIFT) do not provide strong support for or against an impact to the n ormal function of the protein. In summary, based upon the 3 observations in the general population and the 8 observations in individuals without a RASopathy dia gnosis, this variant is likely benign (Grant 2018). ACMG/AMP criteria applied: B S1_Supporting, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 06, 2019 | Variant summary: BRAF c.622A>G (p.Ile208Val) results in a conservative amino acid change located in the Raf-like Ras-binding domain (IPR003116) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.622A>G has been reported in the literature in unaffected individuals and index cases with clinical features inconsistent with a RASopathy in families undergoing evaluation for Noonan Syndrome and Related Conditions (Grant_2018). The variant was also identified in the paternal specimen following its initial identification in a prenatal specimen undergoing evaluation for Noonan syndrome and Related conditions at our laboratory. These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. Co-occurrences with other pathogenic variant(s) have been reported in a melanoma cell line ( BRAF c.1799T>A, p.Val600Glu), providing supporting evidence for a benign role (Ikediobi_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 21, 2019 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2019 | This variant is associated with the following publications: (PMID: 29945942) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at