Genetic Variant NM_144590.3:c.397T>G (chr10-88826040-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144590.3(ANKRD22):c.397T>G(p.Cys133Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 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. C133R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANKRD22
NM_144590.3 missense, splice_region

Scores

Splicing: ADA: 0.0006202

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81

Publications

0 publications found

Variant links:

Genes affected

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

ANKRD22 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15783975).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144590.3. 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
	ANKRD22	NM_144590.3	MANE Select	c.397T>G	p.Cys133Gly	missense splice_region	Exon 4 of 6	NP_653191.2	Q5VYY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD22	ENST00000371930.5	TSL:1 MANE Select	c.397T>G	p.Cys133Gly	missense splice_region	Exon 4 of 6	ENSP00000360998.4	Q5VYY1
	ANKRD22	ENST00000892167.1		c.280T>G	p.Cys94Gly	missense splice_region	Exon 3 of 5	ENSP00000562226.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724870

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33334

American (AMR)

AF:

0.00

AC:

AN:

44176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

85622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108982

Other (OTH)

AF:

0.00

AC:

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.00052

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.0029

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.55

M_CAP

Benign

0.022

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.51

PhyloP100

2.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

REVEL

Benign

0.20

Sift

Benign

0.63

Sift4G

Benign

0.44

Polyphen

0.085

Vest4

0.47

MutPred

0.52

Gain of catalytic residue at C133 (P = 0.0649)

MVP

0.41

MPC

0.19

ClinPred

0.32

GERP RS

5.5

Varity_R

0.19

gMVP

0.29

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00062

dbscSNV1_RF

Benign

0.028

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over