18-9254513-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015208.5(ANKRD12):c.1246C>A(p.Gln416Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,387,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ANKRD12 NM_015208.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

Genes affected

ANKRD12 (HGNC:29135): (ankyrin repeat domain 12) This gene encodes a member of the ankyrin repeats-containing cofactor family. These proteins may inhibit the transcriptional activity of nuclear receptors through the recruitment of histone deacetylases. The encoded protein interacts with p160 coactivators and also represses transcription mediated by the coactivator alteration/deficiency in activation 3 (ADA3). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27208805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD12	NM_015208.5	c.1246C>A	p.Gln416Lys	missense_variant	9/13	ENST00000262126.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD12	ENST00000262126.9	c.1246C>A	p.Gln416Lys	missense_variant	9/13	1	NM_015208.5	P4
ANKRD12	ENST00000400020.7	c.1177C>A	p.Gln393Lys	missense_variant	8/12	1		A2
ANKRD12	ENST00000359158.7	c.*360C>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000151 AC: 21 AN: 1387452 Hom.: 0 Cov.: 32 AF XY: 0.0000117 AC XY: 8 AN XY: 686318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000185

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.1246C>A (p.Q416K) alteration is located in exon 9 (coding exon 8) of the ANKRD12 gene. This alteration results from a C to A substitution at nucleotide position 1246, causing the glutamine (Q) at amino acid position 416 to be replaced by a lysine (K). 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	0.22
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0085	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.10	N;.
REVEL	Benign	0.20
Sift	Benign	0.033	D;.
Sift4G	Benign	1.0	T;T
Polyphen		0.99	D;D
Vest4		0.43
MutPred		0.29		Gain of methylation at Q416 (P = 0.0087);.;
MVP		0.30
ClinPred		0.34	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.10

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: rs755916069; hg19: chr18-9254511; COSMIC: COSV50829354; COSMIC: COSV50829354;