Variant chr10-133326946-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015722.4(CALY):c.292T>C(p.Cys98Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CALY
NM_015722.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.789

Variant links:

Genes affected

CALY (HGNC:17938): (calcyon neuron specific vesicular protein) The protein encoded by this gene is a type II single transmembrane protein. It is required for maximal stimulated calcium release after stimulation of purinergic or muscarinic but not beta-adrenergic receptors. The encoded protein interacts with D1 dopamine receptor and may interact with other DA receptor subtypes and/or GPCRs. [provided by RefSeq, Jul 2008]

CALY links:

ZNF511-PRAP1 (HGNC:38088): (ZNF511-PRAP1 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ZNF511 (zinc finger protein 511) and PRAP1 (proline-rich acidic protein 1) genes on chromosome 10. The putative readthrough transcript may encode a fusion protein that shares sequence identity with each individual gene product and may be involved in the regulation of gene promoters, particularly those found on transfected plasmids. [provided by RefSeq, Apr 2017]

ZNF511-PRAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALY	NM_015722.4 linkuse as main transcript	c.292T>C	p.Cys98Arg	missense_variant	4/6	ENST00000252939.9	NP_056537.1	Q9NYX4-1
CALY	NM_001321617.2 linkuse as main transcript	c.-115T>C		5_prime_UTR_variant	4/6		NP_001308546.1
ZNF511-PRAP1	NM_001396060.1 linkuse as main transcript	c.680+15105A>G		intron_variant			NP_001382989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CALY	ENST00000252939.9 linkuse as main transcript	c.292T>C	p.Cys98Arg	missense_variant	4/6	1	NM_015722.4	ENSP00000252939.4	Q9NYX4-1
ZNF511-PRAP1	ENST00000368554.8 linkuse as main transcript	c.506+15105A>G		intron_variant		2		ENSP00000357542.5	H7BY64
CALY	ENST00000368558.1 linkuse as main transcript	c.292T>C	p.Cys98Arg	missense_variant	4/5	5		ENSP00000357546.1	Q9NYX4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458908

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725462

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2024

The c.292T>C (p.C98R) alteration is located in exon 4 (coding exon 3) of the CALY gene. This alteration results from a T to C substitution at nucleotide position 292, causing the cysteine (C) at amino acid position 98 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-8.3

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.81

MutPred

0.92

Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);

MVP

0.70

MPC

1.9

ClinPred

1.0

GERP RS

4.3

Varity_R

0.93

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over