NM_052853.4:c.124C>T

Variant names:

• chr7-140673454-C-T
• rs140971515
• NM_052853.4:c.124C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_052853.4(ADCK2):​c.124C>T​(p.Leu42Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,608,808 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L42H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (31 hom.)
• Consequence: ADCK2 NM_052853.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0240
• Publications: 5 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]

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056689084).
• BP6: Variant 7-140673454-C-T is Benign according to our data. Variant chr7-140673454-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2658020.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052853.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCK2	NM_052853.4	MANE Select	c.124C>T	p.Leu42Phe	missense	Exon 1 of 8	NP_443085.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCK2	ENST00000072869.9	TSL:1 MANE Select	c.124C>T	p.Leu42Phe	missense	Exon 1 of 8	ENSP00000072869.4	Q7Z695
	ADCK2	ENST00000476491.5	TSL:1	c.124C>T	p.Leu42Phe	missense	Exon 1 of 8	ENSP00000420512.1	C9JE15
	ADCK2	ENST00000926717.1		c.124C>T	p.Leu42Phe	missense	Exon 1 of 9	ENSP00000596776.1

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 525 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00393 AC: 932 AN: 237314 AF XY: 0.00399

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00185

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.00608

Gnomad OTH exome AF: 0.00564

GnomAD4 exome AF: 0.00555 AC: 8078 AN: 1456508 Hom.: 31 Cov.: 31 AF XY: 0.00554 AC XY: 4014 AN XY: 724172

African (AFR) AF: 0.00108 AC: 36 AN: 33384

American (AMR) AF: 0.00262 AC: 116 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 40 AN: 26018

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39556

South Asian (SAS) AF: 0.00265 AC: 227 AN: 85680

European-Finnish (FIN) AF: 0.00161 AC: 83 AN: 51640

Middle Eastern (MID) AF: 0.00366 AC: 21 AN: 5742

European-Non Finnish (NFE) AF: 0.00653 AC: 7244 AN: 1110118

Other (OTH) AF: 0.00516 AC: 310 AN: 60100

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74466

African (AFR) AF: 0.00149 AC: 62 AN: 41584

American (AMR) AF: 0.00124 AC: 19 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00579 AC: 394 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00515 Hom.: 5

Bravo AF: 0.00345

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00642 AC: 55

ExAC AF: 0.00431 AC: 521

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.024
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.014
Sift	Benign	0.20	T
Sift4G	Benign	0.17	T
Polyphen		0.053	B
Vest4		0.15
MVP		0.35
MPC		0.55
ClinPred		0.0041	T
GERP RS		2.7
PromoterAI		0.022	Neutral
Varity_R		0.070
gMVP		0.24
Mutation Taster		=90/10	polymorphism

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: rs140971515; hg19: chr7-140373254;