Genetic Variant ANKMY2:p.Glu423Lys (chr7-16600820-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020319.3(ANKMY2):c.1267G>A(p.Glu423Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

ANKMY2
NM_020319.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

Variant links:

Genes affected

ANKMY2 (HGNC:25370): (ankyrin repeat and MYND domain containing 2) Predicted to enable enzyme binding activity and metal ion binding activity. Predicted to be located in cilium. [provided by Alliance of Genome Resources, Apr 2022]

ANKMY2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011131823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKMY2	NM_020319.3 link	c.1267G>A	p.Glu423Lys	missense_variant	Exon 10 of 10	ENST00000306999.7	NP_064715.1	Q8IV38A0A024R9Z6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKMY2	ENST00000306999.7 link	c.1267G>A	p.Glu423Lys	missense_variant	Exon 10 of 10	1	NM_020319.3	ENSP00000303570.2	Q8IV38
ANKMY2	ENST00000447802.3 link	n.*353G>A		non_coding_transcript_exon_variant	Exon 11 of 11	2		ENSP00000392259.1	G3V0G5
ANKMY2	ENST00000447802.3 link	n.*353G>A		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000392259.1	G3V0G5

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250678

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135506

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461528

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000604

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00205

Gnomad4 AMR

AF:

0.000196

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:

0.000473

Alfa

AF:

0.0000921

Hom.:

Bravo

AF:

0.000559

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000577

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

Jan 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1267G>A (p.E423K) alteration is located in exon 10 (coding exon 10) of the ANKMY2 gene. This alteration results from a G to A substitution at nucleotide position 1267, causing the glutamic acid (E) at amino acid position 423 to be replaced by a lysine (K). 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

0.062

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.00069

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.72

M_CAP

Benign

0.018

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.71

REVEL

Benign

0.064

Sift

Benign

0.17

Sift4G

Benign

0.085

Polyphen

0.024

Vest4

0.082

MVP

0.47

MPC

0.050

ClinPred

0.0082

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.22

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