6-116511890-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_153711.5(CALHM5):c.194T>C(p.Leu65Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,070 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0071 ( 6 hom., cov: 32)

Exomes 𝑓: 0.012 ( 128 hom. )

Consequence

CALHM5
NM_153711.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.41

Variant links:

Genes affected

CALHM5 (HGNC:21568): (calcium homeostasis modulator family member 5) Predicted to enable cation channel activity. Predicted to be involved in cation transmembrane transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CALHM5 links:

TRAPPC3L (HGNC:21090): (trafficking protein particle complex subunit 3L) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport and intra-Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC3L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010640413).

BP6

Variant 6-116511890-T-C is Benign according to our data. Variant chr6-116511890-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2482980.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM5	NM_153711.5 link	c.194T>C	p.Leu65Pro	missense_variant	Exon 1 of 2	ENST00000368599.4	NP_714922.1	Q8N5C1
TRAPPC3L	NM_001139444.3 link	c.241-11224A>G		intron_variant	Intron 3 of 4	ENST00000368602.4	NP_001132916.1	Q5T215-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CALHM5	ENST00000368599.4 link	c.194T>C	p.Leu65Pro	missense_variant	Exon 1 of 2	1	NM_153711.5	ENSP00000357588.3	Q8N5C1
TRAPPC3L	ENST00000368602.4 link	c.241-11224A>G		intron_variant	Intron 3 of 4	5	NM_001139444.3	ENSP00000357591.3	Q5T215-1
TRAPPC3L	ENST00000437098.5 link	c.199-11224A>G		intron_variant	Intron 2 of 3	3		ENSP00000395769.1	A0A0A0MSL6
TRAPPC3L	ENST00000356128.4 link	c.-13+304A>G		intron_variant	Intron 1 of 2	2		ENSP00000348445.4	Q5T215-2

Frequencies

GnomAD3 genomes

AF:

0.00706

AC:

1074

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00518

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00681

AC:

1709

AN:

250974

Hom.:

AF XY:

0.00695

AC XY:

942

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00449

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.00768

GnomAD4 exome

AF:

0.0119

AC:

17327

AN:

1461816

Hom.:

128

Cov.:

AF XY:

0.0115

AC XY:

8341

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.00468

Gnomad4 ASJ exome

AF:

0.00272

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00107

Gnomad4 FIN exome

AF:

0.00330

Gnomad4 NFE exome

AF:

0.0144

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.00705

AC:

1074

AN:

152254

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

470

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00272

Gnomad4 AMR

AF:

0.00517

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00715

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00675

AC:

820

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0120

EpiControl

AF:

0.0110

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 10, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.98

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.99

Vest4

0.84

MVP

0.19

MPC

0.64

ClinPred

0.022

GERP RS

5.5

Varity_R

0.90

gMVP

0.92

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

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