6-36678576-G-C

Variant names:

• chr6-36678576-G-C
• rs4135239
• NM_001291549.3:c.97+643G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291549.3(CDKN1A):​c.97+643G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 816,664 control chromosomes in the GnomAD database, including 6,305 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1093 hom., cov: 32)
  • Exomes 𝑓: 0.12 (5212 hom.)
• Consequence: CDKN1A NM_001291549.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	NM_001291549.3		c.97+643G>C		intron	N/A	NP_001278478.1
	CDKN1A	NM_001374509.1		c.97+643G>C		intron	N/A	NP_001361438.1
	CDKN1A	NM_001374510.1		c.34+2006G>C		intron	N/A	NP_001361439.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	ENST00000448526.6	TSL:3	c.-6+643G>C		intron	N/A	ENSP00000409259.3
	CDKN1A	ENST00000615513.4	TSL:2	c.-6+2052G>C		intron	N/A	ENSP00000482768.1
	CDKN1A	ENST00000459970.1	TSL:5	n.189+643G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17096 AN: 152066 Hom.: 1093 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.122 AC: 81253 AN: 664480 Hom.: 5212 Cov.: 8 AF XY: 0.122 AC XY: 37617 AN XY: 309094

African (AFR) AF: 0.0610 AC: 773 AN: 12664

American (AMR) AF: 0.0990 AC: 79 AN: 798

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 820 AN: 4084

East Asian (EAS) AF: 0.123 AC: 349 AN: 2844

South Asian (SAS) AF: 0.0575 AC: 765 AN: 13312

European-Finnish (FIN) AF: 0.150 AC: 33 AN: 220

Middle Eastern (MID) AF: 0.149 AC: 197 AN: 1322

European-Non Finnish (NFE) AF: 0.125 AC: 75777 AN: 607538

Other (OTH) AF: 0.113 AC: 2460 AN: 21698

GnomAD4 genome AF: 0.112 AC: 17097 AN: 152184 Hom.: 1093 Cov.: 32 AF XY: 0.115 AC XY: 8527 AN XY: 74410

African (AFR) AF: 0.0715 AC: 2970 AN: 41546

American (AMR) AF: 0.102 AC: 1559 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3468

East Asian (EAS) AF: 0.107 AC: 554 AN: 5176

South Asian (SAS) AF: 0.0507 AC: 245 AN: 4828

European-Finnish (FIN) AF: 0.148 AC: 1572 AN: 10602

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.134 AC: 9071 AN: 67942

Other (OTH) AF: 0.112 AC: 236 AN: 2116

Alfa AF: 0.130 Hom.: 191

Bravo AF: 0.109

Asia WGS AF: 0.0700 AC: 243 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.68
PhyloP100		-0.26
PromoterAI		-0.060	Neutral
Mutation Taster		=100/0	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: rs4135239; hg19: chr6-36646353; COSMIC: COSV55191786; COSMIC: COSV55191786;