rs2288474

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_054027.6(ANKH):c.963A>G(p.Ala321Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,956 control chromosomes in the GnomAD database, including 3,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 420 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2710 hom. )

Consequence

ANKH
NM_054027.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.92

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

chondrocalcinosis 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
craniometaphyseal dysplasia, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
skeletal dysplasia
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
craniometaphyseal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ANKH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 5-14741875-T-C is Benign according to our data. Variant chr5-14741875-T-C is described in ClinVar as Benign. ClinVar VariationId is 351512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6 link	c.963A>G	p.Ala321Ala	synonymous_variant	Exon 8 of 12	ENST00000284268.8	NP_473368.1	Q9HCJ1-1
ANKH	XM_017009644.3 link	c.879A>G	p.Ala293Ala	synonymous_variant	Exon 8 of 12		XP_016865133.1
ANKH	XM_011514067.2 link	c.963A>G	p.Ala321Ala	synonymous_variant	Exon 8 of 9		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKH	ENST00000284268.8 link	c.963A>G	p.Ala321Ala	synonymous_variant	Exon 8 of 12	1	NM_054027.6	ENSP00000284268.6	Q9HCJ1-1
ANKH	ENST00000503939.5 link	n.475A>G		non_coding_transcript_exon_variant	Exon 5 of 6	3
ANKH	ENST00000515517.1 link	n.197A>G		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0636

AC:

9676

AN:

152136

Hom.:

416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0828

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.0485

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0443

Gnomad OTH

AF:

0.0621

GnomAD2 exomes

AF:

0.0704

AC:

17709

AN:

251412

AF XY:

0.0647

show subpopulations

Gnomad AFR exome

AF:

0.0811

Gnomad AMR exome

AF:

0.182

Gnomad ASJ exome

AF:

0.0270

Gnomad EAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.0324

Gnomad NFE exome

AF:

0.0444

Gnomad OTH exome

AF:

0.0525

GnomAD4 exome

AF:

0.0516

AC:

75462

AN:

1461702

Hom.:

2710

Cov.:

AF XY:

0.0511

AC XY:

37153

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.0799

AC:

2674

AN:

33474

American (AMR)

AF:

0.175

AC:

7809

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

644

AN:

26132

East Asian (EAS)

AF:

0.146

AC:

5789

AN:

39694

South Asian (SAS)

AF:

0.0506

AC:

4365

AN:

86248

European-Finnish (FIN)

AF:

0.0344

AC:

1839

AN:

53412

Middle Eastern (MID)

AF:

0.0340

AC:

196

AN:

5768

European-Non Finnish (NFE)

AF:

0.0442

AC:

49109

AN:

1111878

Other (OTH)

AF:

0.0503

AC:

3037

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3490

6979

10469

13958

17448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1972

3944

5916

7888

9860

<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:

0.0637

AC:

9697

AN:

152254

Hom.:

420

Cov.:

AF XY:

0.0639

AC XY:

4758

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0831

AC:

3450

AN:

41538

American (AMR)

AF:

0.115

AC:

1756

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3472

East Asian (EAS)

AF:

0.123

AC:

638

AN:

5174

South Asian (SAS)

AF:

0.0485

AC:

234

AN:

4824

European-Finnish (FIN)

AF:

0.0313

AC:

332

AN:

10620

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0443

AC:

3013

AN:

68014

Other (OTH)

AF:

0.0620

AC:

131

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

445

891

1336

1782

2227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0510

Hom.:

402

Bravo

AF:

0.0725

Asia WGS

AF:

0.0850

AC:

293

AN:

3478

EpiCase

AF:

0.0419

EpiControl

AF:

0.0382

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Craniometaphyseal dysplasia, autosomal dominant

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Chondrocalcinosis 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.080

(source)

DANN

Benign

0.40

PhyloP100

-4.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over