9-38586184-T-C

Position:

• chr9-38586184-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_147195.4(ANKRD18A):​c.2246A>G​(p.Lys749Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANKRD18A NM_147195.4 missense, splice_region
• Scores: Splicing: ADA: 0.9681
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

Genes affected

ANKRD18A (HGNC:23643): (ankyrin repeat domain 18A)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD18A	NM_147195.4	c.2246A>G	p.Lys749Arg	missense_variant, splice_region_variant	12/16	ENST00000399703.6	NP_671728.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD18A	ENST00000399703.6	c.2246A>G	p.Lys749Arg	missense_variant, splice_region_variant	12/16	1	NM_147195.4	ENSP00000382610	A2
ANKRD18A	ENST00000602295.5	c.416A>G	p.Lys139Arg	missense_variant, splice_region_variant	4/8	1		ENSP00000473463
ANKRD18A	ENST00000703205.1	c.2432A>G	p.Lys811Arg	missense_variant, splice_region_variant	14/18			ENSP00000515234	P2
ANKRD18A	ENST00000703204.1	c.*1206A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	9/17			ENSP00000515233

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 26, 2022

The c.2246A>G (p.K749R) alteration is located in exon 12 (coding exon 12) of the ANKRD18A gene. This alteration results from a A to G substitution at nucleotide position 2246, causing the lysine (K) at amino acid position 749 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0039	.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	.;N
REVEL	Benign	0.096
Sift	Benign	0.15	.;T
Sift4G	Benign	0.32	T;T
Polyphen		0.19	.;B
Vest4		0.14
MutPred		0.20		.;Loss of methylation at K749 (P = 0.0384);
MVP		0.014
MPC		0.026
ClinPred		0.38	T
GERP RS		1.1
Varity_R		0.078
gMVP		0.047

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.020		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: rs1824372754; hg19: chr9-38586181;