6-36684374-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000389.5(CDKN1A):c.273A>T(p.Gly91=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,613,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: CDKN1A NM_000389.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.118

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-36684374-A-T is Benign according to our data. Variant chr6-36684374-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206063.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-36684374-A-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.118 with no splicing effect.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1A	NM_000389.5	c.273A>T	p.Gly91=	synonymous_variant	2/3	ENST00000244741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000244741.10	c.273A>T	p.Gly91=	synonymous_variant	2/3	1	NM_000389.5	P1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152060 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000493 AC: 122 AN: 247672 Hom.: 0 AF XY: 0.000492 AC XY: 66 AN XY: 134236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000758

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.000459

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.000430

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000273 AC: 399 AN: 1460996 Hom.: 1 Cov.: 33 AF XY: 0.000294 AC XY: 214 AN XY: 726778

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000896

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152180 Hom.: 1 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74398

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000605 Hom.: 0

Bravo AF: 0.000419

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CDKN1A: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.4
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs143676546; hg19: chr6-36652151; COSMIC: COSV104391880; COSMIC: COSV104391880;