Genetic Variant ANKRD36:p.Glu977Lys (chr2-97202363-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001354587.1(ANKRD36):c.2929G>A(p.Glu977Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 151,816 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 40)

Exomes 𝑓: 0.00011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ANKRD36
NM_001354587.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.303

Variant links:

Genes affected

ANKRD36 (HGNC:24079): (ankyrin repeat domain 36)

ANKRD36 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006356925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD36	NM_001354587.1 link	c.2929G>A	p.Glu977Lys	missense_variant	Exon 48 of 76	ENST00000420699.9	NP_001341516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKRD36	ENST00000420699.9 link	c.2929G>A	p.Glu977Lys	missense_variant	Exon 48 of 76	5	NM_001354587.1	ENSP00000391950.4	A6QL64-1
ANKRD36	ENST00000461153.7 link	c.2929G>A	p.Glu977Lys	missense_variant	Exon 48 of 75	5		ENSP00000419530.3	A6QL64-1
ANKRD36	ENST00000652721.1 link	c.2929G>A	p.Glu977Lys	missense_variant	Exon 48 of 76			ENSP00000498611.1	A6QL64-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000763

AC:

AN:

170366

AF XY:

0.0000880

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000421

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000105

AC:

148

AN:

1407040

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

695948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31710

American (AMR)

AF:

0.00

AC:

AN:

36670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25310

East Asian (EAS)

AF:

0.00

AC:

AN:

36444

South Asian (SAS)

AF:

0.0000625

AC:

AN:

80012

European-Finnish (FIN)

AF:

0.0000220

AC:

AN:

45556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.000122

AC:

133

AN:

1087082

Other (OTH)

AF:

0.000154

AC:

AN:

58570

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.000171

AC:

AN:

151816

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41364

American (AMR)

AF:

0.000263

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67880

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome 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

Alfa

AF:

0.0000843

Hom.:

ExAC

AF:

0.0000177

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0019

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.8

.;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.022

.;B

Vest4

0.17

MutPred

0.32

Gain of ubiquitination at E977 (P = 0.0025);Gain of ubiquitination at E977 (P = 0.0025);

MVP

0.31

ClinPred

0.068

GERP RS

-0.66

Varity_R

0.085

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over