Variant rs121908409 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3PP5_Moderate

The NM_054027.6(ANKH):c.14C>T(p.Pro5Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ANKH
NM_054027.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

ANKH (HGNC:15492): (ANKH inorganic pyrophosphate transport regulator) This gene encodes a multipass transmembrane protein that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. Progressive ankylosis-mediated control of pyrophosphate levels has been suggested as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals. Mutations in this gene have been associated with autosomal dominant craniometaphyseal dysplasia. [provided by RefSeq, Jul 2008]

ANKH links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANKH. . Gene score misZ 2.3499 (greater than the threshold 3.09). Trascript score misZ 3.5351 (greater than threshold 3.09). GenCC has associacion of gene with chondrocalcinosis 2, craniometaphyseal dysplasia, autosomal dominant, craniometaphyseal dysplasia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 5-14871434-G-A is Pathogenic according to our data. Variant chr5-14871434-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5198.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-14871434-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKH	NM_054027.6 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant	1/12	ENST00000284268.8	NP_473368.1
ANKH	XM_011514067.2 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant	1/9		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant	1/12	1	NM_054027.6	ENSP00000284268	P1	Q9HCJ1-1
ANKH	ENST00000513115.1 linkuse as main transcript	n.39C>T		non_coding_transcript_exon_variant	1/2	2
ANKH	ENST00000505140.1 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant, NMD_transcript_variant	1/2	5		ENSP00000426332

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 03, 2024

Reported in a patient with chondrocalcinosis in published literature (PMID: 12297989); Published functional studies demonstrate this variant leads to delayed localization and increased expression (PMID: 15818664, 32366894); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17067391, 19088867, 13130483, 24747173, 15818664, 32366894, 20186813, 12297989) -

Chondrocalcinosis 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.46

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.51

Vest4

0.68

MutPred

0.70

Loss of disorder (P = 0.0202);

MVP

0.87

MPC

2.0

ClinPred

0.93

GERP RS

3.2

Varity_R

0.43

gMVP

0.78

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