6-36684194-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000389.5(CDKN1A):c.93C>A(p.Ser31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0989 in 1,611,622 control chromosomes in the GnomAD database, including 14,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. S31S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2560 hom., cov: 32)
  • Exomes 𝑓: 0.094 (12001 hom.)
• Consequence: CDKN1A NM_000389.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.899

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.681613E-4).
• BP6: Variant 6-36684194-C-A is Benign according to our data. Variant chr6-36684194-C-A is described in ClinVar as [Benign]. Clinvar id is 17565.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-36684194-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1A	NM_000389.5	c.93C>A	p.Ser31Arg	missense_variant	2/3	ENST00000244741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000244741.10	c.93C>A	p.Ser31Arg	missense_variant	2/3	1	NM_000389.5	P1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22686 AN: 152110 Hom.: 2560 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0601

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0658

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.154 AC: 38469 AN: 249318 Hom.: 5612 AF XY: 0.140 AC XY: 18941 AN XY: 134984

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.0891

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0655

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0937 AC: 136706 AN: 1459394 Hom.: 12001 Cov.: 33 AF XY: 0.0924 AC XY: 67077 AN XY: 726132

Gnomad4 AFR exome AF: 0.256

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.0904

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.0557

Gnomad4 NFE exome AF: 0.0653

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.149 AC: 22716 AN: 152228 Hom.: 2560 Cov.: 32 AF XY: 0.153 AC XY: 11402 AN XY: 74430

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.0841

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.0601

Gnomad4 NFE AF: 0.0657

Gnomad4 OTH AF: 0.141

Alfa AF: 0.0887 Hom.: 2061

Bravo AF: 0.175

TwinsUK AF: 0.0720 AC: 267

ALSPAC AF: 0.0669 AC: 258

ESP6500AA AF: 0.240 AC: 1057

ESP6500EA AF: 0.0700 AC: 602

ExAC AF: 0.146 AC: 17769

Asia WGS AF: 0.258 AC: 897 AN: 3478

EpiCase AF: 0.0693

EpiControl AF: 0.0661

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CIP1/WAF1 TUMOR-ASSOCIATED POLYMORPHISM 1 Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	2.4
Dann	Benign	0.85
DEOGEN2	Benign	0.049	T;T;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.00027	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.33	T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.22
MutPred		0.12		Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);
MPC		0.19
ClinPred		0.0071	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.49

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: rs1801270; hg19: chr6-36651971; COSMIC: COSV55187247; COSMIC: COSV55187247;