rs762623

Variant names:

• chr6-36677689-G-A
• rs762623
• NM_001291549.3:c.-141-7G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291549.3(CDKN1A):​c.-141-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 425,748 control chromosomes in the GnomAD database, including 3,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1179 hom., cov: 31)
  • Exomes 𝑓: 0.12 (2093 hom.)
• Consequence: CDKN1A NM_001291549.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.889

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_001291549.3	c.-141-7G>A		splice_region_variant, intron_variant	Intron 1 of 3		NP_001278478.1
CDKN1A	NM_001374509.1	c.-49-99G>A		intron_variant	Intron 1 of 3		NP_001361438.1
CDKN1A	NM_001374510.1	c.34+1119G>A		intron_variant	Intron 1 of 2		NP_001361439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000448526.6	c.-37-213G>A		intron_variant	Intron 1 of 3	3		ENSP00000409259.3
CDKN1A	ENST00000615513.4	c.-6+1165G>A		intron_variant	Intron 1 of 2	2		ENSP00000482768.1
DINOL	ENST00000643333.1	n.871C>T		non_coding_transcript_exon_variant	Exon 1 of 1
CDKN1A	ENST00000459970.1	n.44-99G>A		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17959 AN: 151910 Hom.: 1179 Cov.: 31

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.118 AC: 32190 AN: 273720 Hom.: 2093 Cov.: 3 AF XY: 0.111 AC XY: 16199 AN XY: 145354

Gnomad4 AFR exome AF: 0.0848

Gnomad4 AMR exome AF: 0.0870

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.0585

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.118 AC: 17967 AN: 152028 Hom.: 1179 Cov.: 31 AF XY: 0.119 AC XY: 8840 AN XY: 74272

Gnomad4 AFR AF: 0.0924

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0521

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.117

Alfa AF: 0.132 Hom.: 538

Bravo AF: 0.114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs762623; hg19: chr6-36645466;