Genetic Variant ANKRD2:p.Pro111Leu (chr10-97578382-C-T) – 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_001346793.2(ANKRD2):c.332C>T(p.Pro111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ANKRD2
NM_001346793.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30

Variant links:

Genes affected

ANKRD2 (HGNC:495): (ankyrin repeat domain 2) This gene encodes a protein that belongs to the muscle ankyrin repeat protein (MARP) family. A similar gene in rodents is a component of a muscle stress response pathway and plays a role in the stretch-response associated with slow muscle function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ANKRD2 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=0.2520807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD2	NM_001346793.2 link	c.332C>T	p.Pro111Leu	missense_variant	Exon 3 of 9	ENST00000370655.6	NP_001333722.1	A0A0A0MRN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKRD2	ENST00000370655.6 link	c.332C>T	p.Pro111Leu	missense_variant	Exon 3 of 9	1	NM_001346793.2	ENSP00000359689.1	A0A0A0MRN9
ANKRD2	ENST00000307518.9 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 3 of 9	1		ENSP00000306163.5	Q9GZV1-1
ANKRD2	ENST00000298808.9 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 3 of 8	1		ENSP00000298808.5	Q9GZV1-2
ANKRD2	ENST00000455090.1 link	c.332C>T	p.Pro111Leu	missense_variant	Exon 3 of 8	1		ENSP00000403114.1	Q5T457

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249350

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135278

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461588

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413C>T (p.P138L) alteration is located in exon 3 (coding exon 3) of the ANKRD2 gene. This alteration results from a C to T substitution at nucleotide position 413, causing the proline (P) at amino acid position 138 to be replaced by a leucine (L). 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

0.077

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.079

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.69

N;N;.;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Benign

0.15

Sift

Benign

0.053

T;T;T;T

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

0.91

P;D;.;.

Vest4

0.41

MutPred

0.24

Loss of glycosylation at P138 (P = 0.0162);Loss of glycosylation at P138 (P = 0.0162);.;.;

MVP

0.80

MPC

0.47

ClinPred

0.84

GERP RS

5.3

Varity_R

0.24

gMVP

0.56

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