Genetic Variant ANKLE1:p.Arg12Pro (chr19-17281955-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_152363.6(ANKLE1):c.35G>C(p.Arg12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,381,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ANKLE1
NM_152363.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.148

Publications

0 publications found

Variant links:

Genes affected

ANKLE1 (HGNC:26812): (ankyrin repeat and LEM domain containing 1) Enables endonuclease activity. Involved in positive regulation of response to DNA damage stimulus and protein export from nucleus. Located in cytosol and nucleoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ANKLE1 links:

ENSG00000269307 (HGNC:):

ENSG00000269307 links:

USHBP1 (HGNC:24058): (USH1 protein network component harmonin binding protein 1) Enables PDZ domain binding activity. [provided by Alliance of Genome Resources, Apr 2022]

USHBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3028562).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKLE1	NM_152363.6	MANE Select	c.35G>C	p.Arg12Pro	missense	Exon 1 of 9	NP_689576.6
ANKLE1	NM_001278444.2		c.35G>C	p.Arg12Pro	missense	Exon 1 of 8	NP_001265373.2
ANKLE1	NM_001278445.2		c.-3G>C		5_prime_UTR	Exon 1 of 9	NP_001265374.2	Q8NAG6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKLE1	ENST00000404085.7	TSL:2 MANE Select	c.35G>C	p.Arg12Pro	missense	Exon 1 of 9	ENSP00000384008.3	Q8NAG6-2
ANKLE1	ENST00000394458.7	TSL:1	c.197G>C	p.Arg66Pro	missense	Exon 1 of 9	ENSP00000377971.4	A0A499FJM0
ENSG00000269307	ENST00000596542.1	TSL:2	n.*401-107G>C		intron	N/A	ENSP00000469159.2	M0QXG9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000759

AC:

AN:

131732

AF XY:

0.0000139

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:

0.0000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1381946

Hom.:

Cov.:

AF XY:

0.0000513

AC XY:

AN XY:

681612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31420

American (AMR)

AF:

0.00

AC:

AN:

35532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25078

East Asian (EAS)

AF:

0.00

AC:

AN:

35636

South Asian (SAS)

AF:

0.00

AC:

AN:

79060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5040

European-Non Finnish (NFE)

AF:

0.0000640

AC:

AN:

1077370

Other (OTH)

AF:

0.0000347

AC:

AN:

57684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.0000151

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

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.60

M_CAP

Benign

0.019

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.0

PhyloP100

0.15

PrimateAI

Pathogenic

0.83

Sift4G

Benign

0.20

Vest4

0.58

MVP

0.19

MPC

0.83

ClinPred

0.087

GERP RS

0.020

PromoterAI

0.60

Over-expression

(source)

gMVP

0.76

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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