Genetic Variant ANKRD22:p.Cys133Arg (chr10-88826040-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144590.3(ANKRD22):c.397T>C(p.Cys133Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,609,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C133G) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ANKRD22
NM_144590.3 missense, splice_region

Scores

Splicing: ADA: 0.0007298

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81

Variant links:

Genes affected

ANKRD22 (HGNC:28321): (ankyrin repeat domain 22)

ANKRD22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13311747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD22	NM_144590.3 link	c.397T>C	p.Cys133Arg	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000371930.5	NP_653191.2	Q5VYY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD22	ENST00000371930.5 link	c.397T>C	p.Cys133Arg	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_144590.3	ENSP00000360998.4		Q5VYY1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000403

AC:

AN:

248252

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

134218

show subpopulations

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:

0.000301

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1456802

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724870

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:

0.000222

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.397T>C (p.C133R) alteration is located in exon 4 (coding exon 4) of the ANKRD22 gene. This alteration results from a T to C substitution at nucleotide position 397, causing the cysteine (C) at amino acid position 133 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

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.00043

Eigen

Benign

-0.10

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.020

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.54

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.76

REVEL

Benign

0.16

Sift

Benign

0.19

Sift4G

Benign

0.50

Polyphen

0.40

Vest4

0.45

MutPred

0.49

Loss of catalytic residue at C136 (P = 0.0796);

MVP

0.49

MPC

0.29

ClinPred

0.16

GERP RS

5.5

Varity_R

0.37

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00073

dbscSNV1_RF

Benign

0.0080

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