rs1046515

Variant names:

• chr7-140694787-C-T
• rs1046515
• NM_052853.4:c.1865C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ADCK2	NM_052853.4	c.1865C>T	p.Pro622Leu	missense_variant	Exon 8 of 8	ENST00000072869.9	NP_443085.2
ADCK2	XM_011516675.4	c.1769C>T	p.Pro590Leu	missense_variant	Exon 7 of 7		XP_011514977.1
ADCK2	XM_006716170.5	c.1613C>T	p.Pro538Leu	missense_variant	Exon 7 of 7		XP_006716233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCK2	ENST00000072869.9	c.1865C>T	p.Pro622Leu	missense_variant	Exon 8 of 8	1	NM_052853.4	ENSP00000072869.4

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

GnomAD2 exomes AF: 0.103 AC: 25827 AN: 250334 AF XY: 0.105

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 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

African (AFR) AF: 0.179 AC: 5988 AN: 33476

American (AMR) AF: 0.111 AC: 4939 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2662 AN: 26112

East Asian (EAS) AF: 0.0791 AC: 3139 AN: 39674

South Asian (SAS) AF: 0.199 AC: 17082 AN: 86042

European-Finnish (FIN) AF: 0.0838 AC: 4470 AN: 53344

Middle Eastern (MID) AF: 0.122 AC: 705 AN: 5764

European-Non Finnish (NFE) AF: 0.0675 AC: 75069 AN: 1111596

Other (OTH) AF: 0.0934 AC: 5637 AN: 60364

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

African (AFR) AF: 0.176 AC: 7309 AN: 41514

American (AMR) AF: 0.123 AC: 1878 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 344 AN: 3468

East Asian (EAS) AF: 0.0956 AC: 495 AN: 5176

South Asian (SAS) AF: 0.190 AC: 914 AN: 4820

European-Finnish (FIN) AF: 0.0937 AC: 994 AN: 10606

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0724 AC: 4922 AN: 68010

Other (OTH) AF: 0.105 AC: 222 AN: 2110

Alfa AF: 0.0827 Hom.: 1056

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;.
PhyloP100		-0.088
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
Vest4		0.014
ClinPred		0.0019	T
GERP RS		2.8
Varity_R		0.029
gMVP		0.12
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

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