rs2288474

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	NM_054027.6	MANE Select	c.963A>G	p.Ala321Ala	synonymous	Exon 8 of 12	NP_473368.1	Q9HCJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	ENST00000284268.8	TSL:1 MANE Select	c.963A>G	p.Ala321Ala	synonymous	Exon 8 of 12	ENSP00000284268.6	Q9HCJ1-1
	ANKH	ENST00000887636.1		c.963A>G	p.Ala321Ala	synonymous	Exon 8 of 12	ENSP00000557695.1
	ANKH	ENST00000964374.1		c.963A>G	p.Ala321Ala	synonymous	Exon 8 of 12	ENSP00000634433.1

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

GnomAD2 exomes AF: 0.0704 AC: 17709 AN: 251412 AF XY: 0.0647

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

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

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

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: 68 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: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0443 AC: 3013 AN: 68014

Other (OTH) AF: 0.0620 AC: 131 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Craniometaphyseal dysplasia, autosomal dominant (2)
-	-	1	Chondrocalcinosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.080
DANN	Benign	0.40
PhyloP100		-4.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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