rs1046515

Positions:

• chr7-140694787-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052853.4(ADCK2):​c.1865C>T​(p.Pro622Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0848 in 1,613,182 control chromosomes in the GnomAD database, including 7,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. P622P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1140 hom., cov: 32)
  • Exomes 𝑓: 0.082 (6120 hom.)
• Consequence: ADCK2 NM_052853.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0880

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]

NDUFB2 (HGNC:7697): (NADH:ubiquinone oxidoreductase subunit B2) The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is composed of 45 different subunits. This protein has NADH dehydrogenase activity and oxidoreductase activity. It plays a important role in transfering electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Hydropathy analysis revealed that this subunit and 4 other subunits have an overall hydrophilic pattern, even though they are found within the hydrophobic protein (HP) fraction of complex I. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020677447).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCK2	NM_052853.4	c.1865C>T	p.Pro622Leu	missense_variant	8/8	ENST00000072869.9
ADCK2	XM_011516675.4	c.1769C>T	p.Pro590Leu	missense_variant	7/7
ADCK2	XM_006716170.5	c.1613C>T	p.Pro538Leu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCK2	ENST00000072869.9	c.1865C>T	p.Pro622Leu	missense_variant	8/8	1	NM_052853.4	P1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17159 AN: 152076 Hom.: 1137 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0992

Gnomad EAS AF: 0.0950

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0723

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.103 AC: 25827 AN: 250334 Hom.: 1693 AF XY: 0.105 AC XY: 14234 AN XY: 135318

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0963

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0712

Gnomad OTH exome AF: 0.0959

GnomAD4 exome AF: 0.0819 AC: 119691 AN: 1460988 Hom.: 6120 Cov.: 31 AF XY: 0.0849 AC XY: 61700 AN XY: 726748

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0791

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.0838

Gnomad4 NFE exome AF: 0.0675

Gnomad4 OTH exome AF: 0.0934

GnomAD4 genome AF: 0.113 AC: 17184 AN: 152194 Hom.: 1140 Cov.: 32 AF XY: 0.116 AC XY: 8626 AN XY: 74416

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0992

Gnomad4 EAS AF: 0.0956

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.0937

Gnomad4 NFE AF: 0.0724

Gnomad4 OTH AF: 0.105

Alfa AF: 0.0798 Hom.: 665

Bravo AF: 0.113

TwinsUK AF: 0.0682 AC: 253

ALSPAC AF: 0.0714 AC: 275

ESP6500AA AF: 0.174 AC: 766

ESP6500EA AF: 0.0741 AC: 637

ExAC AF: 0.104 AC: 12659

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.3
DANN	Benign	0.84
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.71	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.011
Sift	Benign	0.085	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0060	B;.
Vest4		0.014
MPC		0.51
ClinPred		0.0019	T
GERP RS		2.8
Varity_R		0.029
gMVP		0.12

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: rs1046515; hg19: chr7-140394587; COSMIC: COSV50781516; COSMIC: COSV50781516;