19-10567150-C-T

Variant names:

• chr19-10567150-C-T
• rs370525024
• NM_001800.4:c.409G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001800.4(CDKN2D):​c.409G>A​(p.Ala137Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A137P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: CDKN2D NM_001800.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 1 publications found

Genes affected

CDKN2D (HGNC:1790): (cyclin dependent kinase inhibitor 2D) The protein encoded by this gene is a member of the INK4 family of cyclin-dependent kinase inhibitors. This protein has been shown to form a stable complex with CDK4 or CDK6, and prevent the activation of the CDK kinases, thus function as a cell growth regulator that controls cell cycle G1 progression. The abundance of the transcript of this gene was found to oscillate in a cell-cycle dependent manner with the lowest expression at mid G1 and a maximal expression during S phase. The negative regulation of the cell cycle involved in this protein was shown to participate in repressing neuronal proliferation, as well as spermatogenesis. Two alternatively spliced variants of this gene, which encode an identical protein, have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03346166).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001800.4. 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
	CDKN2D	NM_001800.4	MANE Select	c.409G>A	p.Ala137Thr	missense	Exon 2 of 2	NP_001791.1	P55273
	CDKN2D	NM_079421.3		c.409G>A	p.Ala137Thr	missense	Exon 3 of 3	NP_524145.1	P55273

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2D	ENST00000393599.3	TSL:1 MANE Select	c.409G>A	p.Ala137Thr	missense	Exon 2 of 2	ENSP00000377224.1	P55273
	CDKN2D	ENST00000335766.2	TSL:1	c.409G>A	p.Ala137Thr	missense	Exon 3 of 3	ENSP00000337056.1	P55273

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251352 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727202

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112004

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74362

African (AFR) AF: 0.000410 AC: 17 AN: 41460

American (AMR) AF: 0.000655 AC: 10 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.62	N
PhyloP100		-1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.086
Sift	Benign	0.61	T
Sift4G	Benign	0.60	T
Polyphen		0.51	P
Vest4		0.076
MVP		0.85
MPC		0.46
ClinPred		0.024	T
GERP RS		3.7
Varity_R		0.19
gMVP		0.26
Mutation Taster		=94/6	polymorphism

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: rs370525024; hg19: chr19-10677826; COSMIC: COSV107361240; COSMIC: COSV107361240;