18-51054932-C-G
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_005359.6(SMAD4):c.606C>G(p.Ala202Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,992 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 Likely benign (★★).
Frequency
Consequence
NM_005359.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.606C>G | p.Ala202Ala | synonymous_variant | Exon 5 of 12 | ENST00000342988.8 | NP_005350.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.606C>G | p.Ala202Ala | synonymous_variant | Exon 5 of 12 | 5 | NM_005359.6 | ENSP00000341551.3 | ||
ENSG00000267699 | ENST00000590722.2 | n.*782C>G | non_coding_transcript_exon_variant | Exon 8 of 9 | 2 | ENSP00000465737.1 | ||||
ENSG00000267699 | ENST00000590722.2 | n.*782C>G | 3_prime_UTR_variant | Exon 8 of 9 | 2 | ENSP00000465737.1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251480Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135914
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727216
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74308
ClinVar
Submissions by phenotype
not provided Benign:2
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Hereditary cancer-predisposing syndrome Benign:2
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not specified Benign:1
Variant summary: SMAD4 c.606C>G alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.606C>G in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 220122). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
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. -
Generalized juvenile polyposis/juvenile polyposis coli Benign:1
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Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Benign:1
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Juvenile polyposis syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at