rs201166295
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_017950.4(CCDC40):c.2227G>A(p.Glu743Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,586 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E743D) has been classified as Likely benign.
Frequency
Consequence
NM_017950.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCDC40 | NM_017950.4 | c.2227G>A | p.Glu743Lys | missense_variant | 13/20 | ENST00000397545.9 | |
CCDC40 | NM_001243342.2 | c.2227G>A | p.Glu743Lys | missense_variant | 13/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCDC40 | ENST00000397545.9 | c.2227G>A | p.Glu743Lys | missense_variant | 13/20 | 5 | NM_017950.4 | P2 | |
CCDC40 | ENST00000574799.5 | n.1764G>A | non_coding_transcript_exon_variant | 9/16 | 1 | ||||
CCDC40 | ENST00000374877.7 | c.2227G>A | p.Glu743Lys | missense_variant | 13/18 | 5 | A2 | ||
CCDC40 | ENST00000572253.5 | n.854G>A | non_coding_transcript_exon_variant | 2/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000957 AC: 236AN: 246618Hom.: 1 AF XY: 0.000679 AC XY: 91AN XY: 134054
GnomAD4 exome AF: 0.000190 AC: 277AN: 1461240Hom.: 1 Cov.: 32 AF XY: 0.000142 AC XY: 103AN XY: 726876
GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13AN XY: 74500
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 15 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 12, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Primary ciliary dyskinesia Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2017 | This alteration is classified as 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at