6-36684352-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000389.5(CDKN1A):c.251G>A(p.Arg84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,613,402 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (24 hom.)
• Consequence: CDKN1A NM_000389.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.663

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005693376).
• BP6: Variant 6-36684352-G-A is Benign according to our data. Variant chr6-36684352-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 790317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-36684352-G-A is described in Lovd as [Likely_benign]. Variant chr6-36684352-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 353 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1A	NM_000389.5	c.251G>A	p.Arg84Gln	missense_variant	2/3	ENST00000244741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000244741.10	c.251G>A	p.Arg84Gln	missense_variant	2/3	1	NM_000389.5	P1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00246 AC: 611 AN: 248472 Hom.: 5 AF XY: 0.00250 AC XY: 337 AN XY: 134640

Gnomad AFR exome AF: 0.000882

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.00191

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00360 AC: 5256 AN: 1461100 Hom.: 24 Cov.: 33 AF XY: 0.00352 AC XY: 2559 AN XY: 726820

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00153

Gnomad4 NFE exome AF: 0.00423

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74480

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00396

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00263 Hom.: 0

Bravo AF: 0.00220

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00274 AC: 333

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CDKN1A: BP4, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.3
Dann	Benign	0.85
DEOGEN2	Benign	0.023	T;T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0057	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.24	B;B;B;B;B
Vest4		0.14
MVP		0.62
MPC		0.20
ClinPred		0.0025	T
GERP RS		2.5
Varity_R		0.064
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34916193; hg19: chr6-36652129; COSMIC: COSV55187542; COSMIC: COSV55187542;