rs267606656

chr5-14716832-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_054027.6(ANKH):c.1015T>C(p.Cys339Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKH NM_054027.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ANKH
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 5-14716832-A-G is Pathogenic according to our data. Variant chr5-14716832-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5200.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-14716832-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKH	NM_054027.6	c.1015T>C	p.Cys339Arg	missense_variant	9/12	ENST00000284268.8
ANKH	XM_017009644.3	c.931T>C	p.Cys311Arg	missense_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKH	ENST00000284268.8	c.1015T>C	p.Cys339Arg	missense_variant	9/12	1	NM_054027.6	P1
ANKH	ENST00000502585.1	n.257T>C		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Craniometaphyseal dysplasia, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	29
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.89
Sift	Benign	0.049	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.83		Gain of MoRF binding (P = 0.0626);
MVP		0.96
MPC		2.6
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.99

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: rs267606656; hg19: chr5-14716941;