rs17250963

Variant names:

• chr5-14752741-G-A
• rs17250963
• NM_054027.6:c.517-1502C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_054027.6(ANKH):​c.517-1502C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 151,798 control chromosomes in the GnomAD database, including 2,749 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2749 hom., cov: 32)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.485
• Publications: 6 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.517-1502C>T		intron_variant	Intron 4 of 11	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.433-1502C>T		intron_variant	Intron 4 of 11		XP_016865133.1
ANKH	XM_011514067.2	c.517-1502C>T		intron_variant	Intron 4 of 8		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.517-1502C>T		intron_variant	Intron 4 of 11	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000503939.5	n.29-1502C>T		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27883 AN: 151682 Hom.: 2748 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.198

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.184 AC: 27895 AN: 151798 Hom.: 2749 Cov.: 32 AF XY: 0.180 AC XY: 13341 AN XY: 74198

African (AFR) AF: 0.234 AC: 9691 AN: 41348

American (AMR) AF: 0.146 AC: 2236 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3468

East Asian (EAS) AF: 0.000779 AC: 4 AN: 5134

South Asian (SAS) AF: 0.0356 AC: 171 AN: 4800

European-Finnish (FIN) AF: 0.189 AC: 1998 AN: 10560

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12682 AN: 67908

Other (OTH) AF: 0.195 AC: 412 AN: 2110

Alfa AF: 0.184 Hom.: 4561

Bravo AF: 0.187

Asia WGS AF: 0.0380 AC: 135 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.60
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17250963; hg19: chr5-14752850;