6-36684451-G-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000389.5(CDKN1A):c.350G>A(p.Cys117Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00332 in 1,614,100 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0035 ( 10 hom. )
Consequence
CDKN1A
NM_000389.5 missense
NM_000389.5 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 4.09
Genes affected
CDKN1A (HGNC:1784): (cyclin dependent kinase inhibitor 1A) This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.076607496).
BP6
Variant 6-36684451-G-A is Benign according to our data. Variant chr6-36684451-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430358.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 287 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDKN1A | NM_000389.5 | c.350G>A | p.Cys117Tyr | missense_variant | 2/3 | ENST00000244741.10 | NP_000380.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN1A | ENST00000244741.10 | c.350G>A | p.Cys117Tyr | missense_variant | 2/3 | 1 | NM_000389.5 | ENSP00000244741.6 |
Frequencies
GnomAD3 genomes AF: 0.00189 AC: 287AN: 152252Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00192 AC: 480AN: 250376Hom.: 0 AF XY: 0.00185 AC XY: 251AN XY: 135448
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GnomAD4 exome AF: 0.00347 AC: 5071AN: 1461730Hom.: 10 Cov.: 33 AF XY: 0.00336 AC XY: 2446AN XY: 727152
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GnomAD4 genome AF: 0.00188 AC: 287AN: 152370Hom.: 1 Cov.: 33 AF XY: 0.00177 AC XY: 132AN XY: 74502
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2017 | The C117Y variant in the CDKN1A gene has been reported previously as a germline variant in an individual with a parathyroid adenoma (Costa-Guda et al., 2013). Functional studies of the C117Y variant did not reveal any effect on the CDKN1A protein structure or function (Costa-Guda et al., 2013). The C117Y variant in the CDKN1A gene has also been previously reported as a somatic variant in B chronic lymphocystic leukemia, but no studies of the germline were done (Athanasakis et al., 2014). The C117Y variant is observed in 194/64940 (0.3%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The C117Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C117Y as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | CDKN1A: BS3:Supporting, BS1 - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;.;.;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;L;L;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;D;D;D
REVEL
Uncertain
Sift
Uncertain
.;.;D;D;D
Sift4G
Benign
T;T;T;T;T
Polyphen
D;D;D;D;D
Vest4
MVP
MPC
0.91
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at