6-36677919-A-G

Variant names:

• chr6-36677919-A-G
• rs2395655
• NM_001291549.3:c.83A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001291549.3(CDKN1A):​c.83A>G​(p.Asp28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,345,436 control chromosomes in the GnomAD database, including 118,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (19399 hom., cov: 31)
  • Exomes 𝑓: 0.40 (99162 hom.)
• Consequence: CDKN1A NM_001291549.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 75 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]

DINOL (HGNC:53146): (damage induced long noncoding RNA)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.17).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291549.3. 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_001291549.3		c.83A>G	p.Asp28Gly	missense	Exon 2 of 4	NP_001278478.1
	CDKN1A	NM_001374509.1		c.83A>G	p.Asp28Gly	missense	Exon 2 of 4	NP_001361438.1
	CDKN1A	NM_078467.3		c.-20A>G		5_prime_UTR	Exon 2 of 4	NP_510867.1	P38936

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	ENST00000448526.6	TSL:3	c.-20A>G		5_prime_UTR	Exon 2 of 4	ENSP00000409259.3	P38936
	CDKN1A	ENST00000911805.1		c.-20A>G		5_prime_UTR	Exon 2 of 4	ENSP00000581864.1
	CDKN1A	ENST00000911806.1		c.-20A>G		5_prime_UTR	Exon 2 of 4	ENSP00000581865.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73846 AN: 151896 Hom.: 19350 Cov.: 31

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.502

GnomAD2 exomes AF: 0.427 AC: 54819 AN: 128402 AF XY: 0.431

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.495

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.401 AC: 478550 AN: 1193422 Hom.: 99162 Cov.: 24 AF XY: 0.403 AC XY: 235478 AN XY: 584570

African (AFR) AF: 0.696 AC: 18893 AN: 27140

American (AMR) AF: 0.341 AC: 10333 AN: 30276

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 11017 AN: 20140

East Asian (EAS) AF: 0.550 AC: 12521 AN: 22780

South Asian (SAS) AF: 0.449 AC: 34368 AN: 76550

European-Finnish (FIN) AF: 0.356 AC: 4671 AN: 13112

Middle Eastern (MID) AF: 0.547 AC: 2618 AN: 4784

European-Non Finnish (NFE) AF: 0.382 AC: 363665 AN: 951816

Other (OTH) AF: 0.437 AC: 20464 AN: 46824

GnomAD4 genome AF: 0.486 AC: 73944 AN: 152014 Hom.: 19399 Cov.: 31 AF XY: 0.486 AC XY: 36088 AN XY: 74288

African (AFR) AF: 0.686 AC: 28419 AN: 41452

American (AMR) AF: 0.427 AC: 6527 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1931 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2686 AN: 5160

South Asian (SAS) AF: 0.456 AC: 2197 AN: 4818

European-Finnish (FIN) AF: 0.361 AC: 3815 AN: 10560

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26903 AN: 67954

Other (OTH) AF: 0.508 AC: 1072 AN: 2110

Alfa AF: 0.438 Hom.: 28789

Bravo AF: 0.498

Asia WGS AF: 0.508 AC: 1768 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.29
PhyloP100		-1.3
Mutation Taster		=99/1	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: rs2395655; hg19: chr6-36645696; COSMIC: COSV55187098; COSMIC: COSV55187098;