11-113399293-G-C

Variant names:

• chr11-113399293-G-C
• rs4938016
• NM_178510.2:c.1324G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_178510.2(ANKK1):​c.1324G>C​(p.Gly442Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,600,436 control chromosomes in the GnomAD database, including 359,034 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G442C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.60 (28188 hom., cov: 34)
  • Exomes 𝑓: 0.67 (330846 hom.)
• Consequence: ANKK1 NM_178510.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236
• Publications: 56 publications found

Genes affected

ANKK1 (HGNC:21027): (ankyrin repeat and kinase domain containing 1) The protein encoded by this gene belongs to the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways. This gene is closely linked to DRD2 gene (GeneID:1813) on chr 11, and a well studied restriction fragment length polymorphism (RFLP) designated TaqIA, was originally associated with the DRD2 gene, however, later was determined to be located in exon 8 of ANKK1 gene (PMIDs: 18621654, 15146457), where it causes a nonconservative amino acid substitution. It is not clear if this gene plays any role in neuropsychiatric disorders previously associated with Taq1A RFLP. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1771816E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKK1	NM_178510.2	c.1324G>C	p.Gly442Arg	missense_variant	Exon 8 of 8	ENST00000303941.4	NP_848605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKK1	ENST00000303941.4	c.1324G>C	p.Gly442Arg	missense_variant	Exon 8 of 8	1	NM_178510.2	ENSP00000306678.3

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91200 AN: 152048 Hom.: 28182 Cov.: 34

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.641 AC: 146108 AN: 227906 AF XY: 0.644

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.675

Gnomad ASJ exome AF: 0.628

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.637

Gnomad NFE exome AF: 0.687

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.673 AC: 974510 AN: 1448270 Hom.: 330846 Cov.: 98 AF XY: 0.672 AC XY: 483406 AN XY: 719012

African (AFR) AF: 0.433 AC: 14365 AN: 33212

American (AMR) AF: 0.666 AC: 28617 AN: 42952

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 16328 AN: 25818

East Asian (EAS) AF: 0.444 AC: 17360 AN: 39122

South Asian (SAS) AF: 0.641 AC: 53580 AN: 83642

European-Finnish (FIN) AF: 0.646 AC: 33583 AN: 51950

Middle Eastern (MID) AF: 0.581 AC: 3346 AN: 5760

European-Non Finnish (NFE) AF: 0.695 AC: 768516 AN: 1105890

Other (OTH) AF: 0.648 AC: 38815 AN: 59924

GnomAD4 genome AF: 0.600 AC: 91238 AN: 152166 Hom.: 28188 Cov.: 34 AF XY: 0.597 AC XY: 44390 AN XY: 74362

African (AFR) AF: 0.447 AC: 18574 AN: 41520

American (AMR) AF: 0.618 AC: 9448 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2215 AN: 3470

East Asian (EAS) AF: 0.457 AC: 2352 AN: 5142

South Asian (SAS) AF: 0.625 AC: 3013 AN: 4824

European-Finnish (FIN) AF: 0.637 AC: 6745 AN: 10592

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.687 AC: 46732 AN: 68000

Other (OTH) AF: 0.633 AC: 1338 AN: 2114

Alfa AF: 0.660 Hom.: 18562

Bravo AF: 0.598

TwinsUK AF: 0.692 AC: 2565

ALSPAC AF: 0.695 AC: 2679

ESP6500AA AF: 0.485 AC: 2069

ESP6500EA AF: 0.695 AC: 5896

ExAC AF: 0.623 AC: 75059

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.024
DANN	Benign	0.40
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.16	N
PhyloP100		-0.24
PrimateAI	Benign	0.19	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.023
Sift	Benign	0.51	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.032
MPC		0.070
ClinPred		0.00068	T
GERP RS		1.8
Varity_R		0.099
gMVP		0.19
Mutation Taster		=98/2	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: rs4938016; hg19: chr11-113270015; COSMIC: COSV58271619; COSMIC: COSV58271619;