chr4-183446307-G-T

Position:

• chr4-183446307-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017632.4(CDKN2AIP):​c.623G>T​(p.Arg208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDKN2AIP NM_017632.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200

Genes affected

CDKN2AIP (HGNC:24325): (CDKN2A interacting protein) The protein encoded by this gene regulates the DNA damage response through several different signaling pathways. One such pathway is the p53-HDM2-p21(WAF1) pathway, which is critical to the DNA damage response. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

CDKN2AIP (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04604125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2AIP	NM_017632.4	c.623G>T	p.Arg208Leu	missense_variant	3/3	ENST00000504169.2	NP_060102.1
CDKN2AIP	NM_001317343.2	c.*211G>T		3_prime_UTR_variant	3/3		NP_001304272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2AIP	ENST00000504169.2	c.623G>T	p.Arg208Leu	missense_variant	3/3	1	NM_017632.4	ENSP00000427108.1
CDKN2AIP	ENST00000302350.4	c.*211G>T		3_prime_UTR_variant	3/3	2		ENSP00000303788.4
CDKN2AIP	ENST00000502924.1	n.167G>T		non_coding_transcript_exon_variant	1/2	3
CDKN2AIP	ENST00000506835.1	n.436G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The c.623G>T (p.R208L) alteration is located in exon 3 (coding exon 3) of the CDKN2AIP gene. This alteration results from a G to T substitution at nucleotide position 623, causing the arginine (R) at amino acid position 208 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.71
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.0090
Sift	Uncertain	0.020	D
Sift4G	Benign	0.29	T
Polyphen		0.020	B
Vest4		0.13
MutPred		0.37		Gain of glycosylation at S209 (P = 0.003);
MVP		0.068
MPC		0.072
ClinPred		0.026	T
GERP RS		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.33

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: rs1733671111; hg19: chr4-184367460;