10-74151299-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006721.4(ADK):c.21G>C(p.Glu7Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,397,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADK NM_006721.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.107

Genes affected

ADK (HGNC:257): (adenosine kinase) This gene an enzyme which catalyzes the transfer of the gamma-phosphate from ATP to adenosine, thereby serving as a regulator of concentrations of both extracellular adenosine and intracellular adenine nucleotides. Adenosine has widespread effects on the cardiovascular, nervous, respiratory, and immune systems and inhibitors of the enzyme could play an important pharmacological role in increasing intravascular adenosine concentrations and acting as anti-inflammatory agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15002102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADK	NM_006721.4	c.21G>C	p.Glu7Asp	missense_variant	1/11	ENST00000539909.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADK	ENST00000539909.6	c.21G>C	p.Glu7Asp	missense_variant	1/11	2	NM_006721.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000192 AC: 3 AN: 156082 Hom.: 0 AF XY: 0.0000122 AC XY: 1 AN XY: 82118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397336 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000840

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.21G>C (p.E7D) alteration is located in exon 1 (coding exon 1) of the ADK gene. This alteration results from a G to C substitution at nucleotide position 21, causing the glutamic acid (E) at amino acid position 7 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Benign	0.97
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.89	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.23
Sift	Benign	0.064	T;D
Sift4G	Benign	0.25	T;T
Polyphen		0.53	.;P
Vest4		0.21
MutPred		0.27		Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);
MVP		0.41
MPC		0.25
ClinPred		0.44	T
GERP RS		-2.7
Varity_R		0.13
gMVP		0.22

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: rs971684446; hg19: chr10-75911057;