18-9254513-C-A

Variant names:

• chr18-9254513-C-A
• rs755916069
• NM_015208.5:c.1246C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 3 publications found

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]

ENSG00000265257 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015208.5. 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
	ANKRD12	NM_015208.5	MANE Select	c.1246C>A	p.Gln416Lys	missense	Exon 9 of 13	NP_056023.3
	ANKRD12	NM_001083625.3		c.1177C>A	p.Gln393Lys	missense	Exon 8 of 12	NP_001077094.1	Q6UB98-2
	ANKRD12	NM_001204056.1		c.1177C>A	p.Gln393Lys	missense	Exon 8 of 12	NP_001190985.1	Q6UB98-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD12	ENST00000262126.9	TSL:1 MANE Select	c.1246C>A	p.Gln416Lys	missense	Exon 9 of 13	ENSP00000262126.3	Q6UB98-1
	ANKRD12	ENST00000400020.7	TSL:1	c.1177C>A	p.Gln393Lys	missense	Exon 8 of 12	ENSP00000382897.3	Q6UB98-2
	ANKRD12	ENST00000917028.1		c.1246C>A	p.Gln416Lys	missense	Exon 9 of 13	ENSP00000587087.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000505 AC: 1 AN: 197902 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29982

American (AMR) AF: 0.00 AC: 0 AN: 28954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22400

East Asian (EAS) AF: 0.00 AC: 0 AN: 38402

South Asian (SAS) AF: 0.00 AC: 0 AN: 73554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5418

European-Non Finnish (NFE) AF: 0.0000185 AC: 20 AN: 1080934

Other (OTH) AF: 0.0000176 AC: 1 AN: 56968

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000051719), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.20
Sift	Benign	0.033	D
Sift4G	Benign	1.0	T
Polyphen		0.99	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
Mutation Taster		=87/13	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: rs755916069; hg19: chr18-9254511; COSMIC: COSV50829354; COSMIC: COSV50829354;