7-140673982-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052853.4(ADCK2):c.652T>C(p.Tyr218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 1 hom. )

Consequence

ADCK2
NM_052853.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Variant links:

Genes affected

ADCK2 (HGNC:19039): (aarF domain containing kinase 2) Predicted to enable ATP binding activity and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ADCK2 links:

DENND2A (HGNC:22212): (DENN domain containing 2A) Enables guanyl-nucleotide exchange factor activity. Involved in retrograde transport, endosome to Golgi. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

DENND2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.020775378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCK2	NM_052853.4 link	c.652T>C	p.Tyr218His	missense_variant	Exon 1 of 8	ENST00000072869.9	NP_443085.2	Q7Z695A4D1T6
ADCK2	XM_011516675.4 link	c.652T>C	p.Tyr218His	missense_variant	Exon 1 of 7		XP_011514977.1
ADCK2	XM_006716170.5 link	c.652T>C	p.Tyr218His	missense_variant	Exon 1 of 7		XP_006716233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADCK2	ENST00000072869.9 link	c.652T>C	p.Tyr218His	missense_variant	Exon 1 of 8	1	NM_052853.4	ENSP00000072869.4	Q7Z695
ADCK2	ENST00000476491.5 link	c.652T>C	p.Tyr218His	missense_variant	Exon 1 of 8	1		ENSP00000420512.1	C9JE15
ADCK2	ENST00000483369.5 link	c.163T>C	p.Tyr55His	missense_variant	Exon 1 of 8	5		ENSP00000417367.1	H7C4I2
DENND2A	ENST00000489552.1 link	c.-254A>G		5_prime_UTR_variant	Exon 1 of 2	4		ENSP00000418088.1	C9JAA0

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251396

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000846

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.652T>C (p.Y218H) alteration is located in exon 1 (coding exon 1) of the ADCK2 gene. This alteration results from a T to C substitution at nucleotide position 652, causing the tyrosine (Y) at amino acid position 218 to be replaced by a histidine (H). 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

0.10

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0055

T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.068

Sift

Benign

0.38

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.047

B;B

Vest4

0.080

MutPred

0.59

Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);

MVP

0.081

MPC

0.63

ClinPred

0.027

GERP RS

2.6

Varity_R

0.047

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over