rs121908410

Positions:

• chr5-14871435-G-A
• chr5-14871435-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP5_Moderate

The NM_054027.6(ANKH):​c.13C>T​(p.Pro5Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKH NM_054027.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.08

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-14871434-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANKH. . Gene score misZ 2.3499 (greater than the threshold 3.09). Trascript score misZ 3.5351 (greater than threshold 3.09). GenCC has associacion of gene with chondrocalcinosis 2, craniometaphyseal dysplasia, autosomal dominant, craniometaphyseal dysplasia.
• PP5: Variant 5-14871435-G-A is Pathogenic according to our data. Variant chr5-14871435-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 974898.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKH	NM_054027.6	c.13C>T	p.Pro5Ser	missense_variant	1/12	ENST00000284268.8	NP_473368.1
ANKH	XM_011514067.2	c.13C>T	p.Pro5Ser	missense_variant	1/9		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.13C>T	p.Pro5Ser	missense_variant	1/12	1	NM_054027.6	ENSP00000284268	P1
ANKH	ENST00000513115.1	n.38C>T		non_coding_transcript_exon_variant	1/2	2
ANKH	ENST00000505140.1	c.13C>T	p.Pro5Ser	missense_variant, NMD_transcript_variant	1/2	5		ENSP00000426332

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chondrocalcinosis 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.67	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.085	B
Vest4		0.63
MutPred		0.64		Gain of glycosylation at P5 (P = 0.0152);
MVP		0.87
MPC		2.0
ClinPred		0.60	D
GERP RS		4.1
Varity_R		0.41
gMVP		0.71

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: rs121908410; hg19: chr5-14871544;