Variant 10-133328015-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015722.4(CALY):c.136G>A(p.Val46Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000556 in 1,595,858 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 2 hom. )

Consequence

CALY
NM_015722.4 missense, splice_region

Scores

Splicing: ADA: 0.9719

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.415

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:):

ZNF511-PRAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07680413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CALY	NM_015722.4 linkuse as main transcript	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/6	ENST00000252939.9
ZNF511-PRAP1	NM_001396060.1 linkuse as main transcript	c.680+16174C>T		intron_variant
CALY	NM_001321617.2 linkuse as main transcript	c.-271G>A		splice_region_variant, 5_prime_UTR_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALY	ENST00000252939.9 linkuse as main transcript	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/6	1	NM_015722.4	P1	Q9NYX4-1
CALY	ENST00000368555.3 linkuse as main transcript	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/3	2			Q9NYX4-3
CALY	ENST00000368558.1 linkuse as main transcript	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/5	5			Q9NYX4-2

Frequencies

GnomAD3 genomes

AF:

0.000650

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000574

AC:

136

AN:

236790

Hom.:

AF XY:

0.000593

AC XY:

AN XY:

128250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000390

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000277

Gnomad FIN exome

AF:

0.000146

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.000344

GnomAD4 exome

AF:

0.000547

AC:

789

AN:

1443534

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

423

AN XY:

718260

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.000341

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000236

Gnomad4 FIN exome

AF:

0.000531

Gnomad4 NFE exome

AF:

0.000641

Gnomad4 OTH exome

AF:

0.000285

GnomAD4 genome

AF:

0.000650

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000879

Hom.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000603

AC:

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

Mar 16, 2022

The c.136G>A (p.V46M) alteration is located in exon 3 (coding exon 2) of the CALY gene. This alteration results from a G to A substitution at nucleotide position 136, causing the valine (V) at amino acid position 46 to be replaced by a methionine (M). 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

Benign

0.25

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.67

D;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.80

T;T;D

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.077

T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.2

M;M;M

MutationTaster

Benign

0.81

D;D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.3

N;N;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.32

MVP

0.26

MPC

0.99

ClinPred

0.075

GERP RS

4.3

Varity_R

0.53

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over