rs1801270

Variant names:

• chr6-36684194-C-A
• rs1801270
• NM_000389.5:c.93C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-36684194-C-A
• chr6-36684194-C-T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 185 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 17565.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000389.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	NM_000389.5	MANE Select	c.93C>A	p.Ser31Arg	missense	Exon 2 of 3	NP_000380.1	P38936
	CDKN1A	NM_001291549.3		c.195C>A	p.Ser65Arg	missense	Exon 3 of 4	NP_001278478.1
	CDKN1A	NM_001374509.1		c.195C>A	p.Ser65Arg	missense	Exon 3 of 4	NP_001361438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	ENST00000244741.10	TSL:1 MANE Select	c.93C>A	p.Ser31Arg	missense	Exon 2 of 3	ENSP00000244741.6	P38936
	CDKN1A	ENST00000405375.5	TSL:1	c.93C>A	p.Ser31Arg	missense	Exon 2 of 3	ENSP00000384849.1	P38936
	CDKN1A	ENST00000373711.4	TSL:5	c.93C>A	p.Ser31Arg	missense	Exon 3 of 4	ENSP00000362815.1	P38936

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

GnomAD2 exomes AF: 0.154 AC: 38469 AN: 249318 AF XY: 0.140

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 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

African (AFR) AF: 0.256 AC: 8568 AN: 33470

American (AMR) AF: 0.332 AC: 14854 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 2362 AN: 26118

East Asian (EAS) AF: 0.480 AC: 19072 AN: 39696

South Asian (SAS) AF: 0.104 AC: 8934 AN: 86252

European-Finnish (FIN) AF: 0.0557 AC: 2848 AN: 51090

Middle Eastern (MID) AF: 0.126 AC: 727 AN: 5768

European-Non Finnish (NFE) AF: 0.0653 AC: 72560 AN: 1111918

Other (OTH) AF: 0.112 AC: 6781 AN: 60382

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

African (AFR) AF: 0.249 AC: 10335 AN: 41538

American (AMR) AF: 0.225 AC: 3438 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0841 AC: 292 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2504 AN: 5148

South Asian (SAS) AF: 0.122 AC: 587 AN: 4826

European-Finnish (FIN) AF: 0.0601 AC: 638 AN: 10616

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0657 AC: 4471 AN: 68012

Other (OTH) AF: 0.141 AC: 298 AN: 2114

Alfa AF: 0.100 Hom.: 5680

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CIP1/WAF1 TUMOR-ASSOCIATED POLYMORPHISM 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.00027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.90
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.12		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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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