chr6-36684451-G-A

Variant names:

• chr6-36684451-G-A
• rs148679597
• NM_000389.5:c.350G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• 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]

ACMG classification

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 rank	MANE	Protein	UniProt
CDKN1A	NM_000389.5	c.350G>A	p.Cys117Tyr	missense_variant	Exon 2 of 3	ENST00000244741.10	NP_000380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000244741.10	c.350G>A	p.Cys117Tyr	missense_variant	Exon 2 of 3	1	NM_000389.5	ENSP00000244741.6

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152252 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00192 AC: 480 AN: 250376 Hom.: 0 AF XY: 0.00185 AC XY: 251 AN XY: 135448

Gnomad AFR exome AF: 0.000558

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00347 AC: 5071 AN: 1461730 Hom.: 10 Cov.: 33 AF XY: 0.00336 AC XY: 2446 AN XY: 727152

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000600

Gnomad4 NFE exome AF: 0.00431

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152370 Hom.: 1 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74502

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00185

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00178 AC: 216

EpiCase AF: 0.00278

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN1A: BS3:Supporting, BS1 -

May 26, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;T;T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.78	.;T;.;.;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Benign	1.7	L;L;L;L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	.;.;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.026	.;.;D;D;D
Sift4G	Benign	0.097	T;T;T;T;T
Polyphen		0.99	D;D;D;D;D
Vest4		0.68
MVP		0.93
MPC		0.91
ClinPred		0.030	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148679597; hg19: chr6-36652228; COSMIC: COSV99781815; COSMIC: COSV99781815;