4-183444967-C-G

Position:

• chr4-183444967-C-G

Variant summary

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

The NM_017632.4(CDKN2AIP):​c.170C>G​(p.Thr57Arg) 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. 14/20 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: 0.334

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]

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=0.050820053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2AIP	NM_017632.4	c.170C>G	p.Thr57Arg	missense_variant	1/3	ENST00000504169.2	NP_060102.1
CDKN2AIP	NM_001317343.2	c.170C>G	p.Thr57Arg	missense_variant	1/3		NP_001304272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2AIP	ENST00000504169.2	c.170C>G	p.Thr57Arg	missense_variant	1/3	1	NM_017632.4	ENSP00000427108.1
CDKN2AIP	ENST00000510928.1	c.170C>G	p.Thr57Arg	missense_variant	1/2	2		ENSP00000421308.1
CDKN2AIP	ENST00000302350.4	c.170C>G	p.Thr57Arg	missense_variant	1/3	2		ENSP00000303788.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Aug 30, 2021

The c.170C>G (p.T57R) alteration is located in exon 1 (coding exon 1) of the CDKN2AIP gene. This alteration results from a C to G substitution at nucleotide position 170, causing the threonine (T) at amino acid position 57 to be replaced by an arginine (R). 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	0.072
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.64
DEOGEN2	Benign	0.0094	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.039
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.097
MutPred		0.17		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.082
MPC		1.2
ClinPred		0.092	T
GERP RS		0.10
Varity_R		0.097
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-184366120;