rs2288474

Variant names:

• chr5-14741875-T-C
• rs2288474
• NM_054027.6:c.963A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.92

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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	c.963A>G	p.Ala321Ala	synonymous_variant	Exon 8 of 12	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.879A>G	p.Ala293Ala	synonymous_variant	Exon 8 of 12		XP_016865133.1
ANKH	XM_011514067.2	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	Appris	UniProt
ANKH	ENST00000284268.8	c.963A>G	p.Ala321Ala	synonymous_variant	Exon 8 of 12	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000503939.5	n.475A>G		non_coding_transcript_exon_variant	Exon 5 of 6	3
ANKH	ENST00000515517.1	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.: 33

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

GnomAD3 exomes AF: 0.0704 AC: 17709 AN: 251412 Hom.: 978 AF XY: 0.0647 AC XY: 8796 AN XY: 135878

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 SAS exome AF: 0.0522

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.: 31 AF XY: 0.0511 AC XY: 37153 AN XY: 727154

Gnomad4 AFR exome AF: 0.0799

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.0506

Gnomad4 FIN exome AF: 0.0344

Gnomad4 NFE exome AF: 0.0442

Gnomad4 OTH exome AF: 0.0503

GnomAD4 genome AF: 0.0637 AC: 9697 AN: 152254 Hom.: 420 Cov.: 33 AF XY: 0.0639 AC XY: 4758 AN XY: 74450

Gnomad4 AFR AF: 0.0831

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.0485

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0620

Alfa AF: 0.0460 Hom.: 244

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

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.080
DANN	Benign	0.40

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

Other links and lift over

dbSNP: rs2288474; hg19: chr5-14741984; COSMIC: COSV52478555;