Genetic Variant ANKRD23:p.Arg291Pro (chr2-96839595-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_144994.8(ANKRD23):c.872G>C(p.Arg291Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 1,485,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

ANKRD23
NM_144994.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.930

Variant links:

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]

ANKRD23 links:

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]

ANKRD39 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ANKRD23	NM_144994.8 link	c.872G>C	p.Arg291Pro	missense_variant	Exon 9 of 9	ENST00000318357.9	NP_659431.5	Q86SG2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD23	ENST00000318357.9 link	c.872G>C	p.Arg291Pro	missense_variant	Exon 9 of 9	1	NM_144994.8	ENSP00000321679.4		Q86SG2-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1333168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

649846

show subpopulations

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:

9.51e-7

Gnomad4 OTH exome

AF:

0.0000182

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.872G>C (p.R291P) alteration is located in exon 9 (coding exon 9) of the ANKRD23 gene. This alteration results from a G to C substitution at nucleotide position 872, causing the arginine (R) at amino acid position 291 to be replaced by a proline (P). 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

0.57

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.75

.;T;T

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.56

P;P;P

Vest4

0.46

MutPred

0.60

Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);.;

MVP

0.36

MPC

0.38

ClinPred

1.0

GERP RS

-4.0

Varity_R

0.49

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over