2-96840441-C-A

Variant names:

• chr2-96840441-C-A
• rs1244839747
• NM_144994.8:c.500G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_144994.8(ANKRD23):​c.500G>T​(p.Gly167Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ANKRD23 NM_144994.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

Genes affected

ANKRD23 (HGNC:24470): (ankyrin repeat domain 23) This gene is a member of the muscle ankyrin repeat protein (MARP) family and encodes a protein with four tandem ankyrin-like repeats. The protein is localized to the nucleus, functioning as a transcriptional regulator. Expression of this protein is induced during recovery following starvation. [provided by RefSeq, Jul 2008]

ANKRD39 (HGNC:28640): (ankyrin repeat domain 39) Predicted to contribute to ubiquitin-protein transferase activity. Predicted to be involved in protein K6-linked ubiquitination. Predicted to be part of BRCA1-A complex and BRCA1-BARD1 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD23	NM_144994.8	c.500G>T	p.Gly167Val	missense_variant	Exon 5 of 9	ENST00000318357.9	NP_659431.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD23	ENST00000318357.9	c.500G>T	p.Gly167Val	missense_variant	Exon 5 of 9	1	NM_144994.8	ENSP00000321679.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250994 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461758 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727184

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500G>T (p.G167V) alteration is located in exon 5 (coding exon 5) of the ANKRD23 gene. This alteration results from a G to T substitution at nucleotide position 500, causing the glycine (G) at amino acid position 167 to be replaced by a valine (V). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.5	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.2	D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.76		Loss of catalytic residue at A166 (P = 0.1042);Loss of catalytic residue at A166 (P = 0.1042);.;
MVP		0.67
MPC		0.73
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.77

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: rs1244839747; hg19: chr2-97506178;