Genetic Variant CALHM6:p.Ser145Arg (chr6-116462362-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001010919.3(CALHM6):c.433A>C(p.Ser145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,452,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CALHM6
NM_001010919.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.15

Variant links:

Genes affected

CALHM6 (HGNC:33391): (calcium homeostasis modulator family member 6) Predicted to enable cation channel activity. Predicted to be involved in cation transmembrane transport. Predicted to be integral component of membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CALHM6 links:

ENSG00000285446 (HGNC:):

ENSG00000285446 links:

CALHM6-AS1 (HGNC:40971): (CALHM6 antisense RNA 1)

CALHM6-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10279372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM6	NM_001010919.3 link	c.433A>C	p.Ser145Arg	missense_variant	Exon 2 of 3	ENST00000368605.3	NP_001010919.1	Q5R3K3-1
CALHM6	XM_011535845.4 link	c.433A>C	p.Ser145Arg	missense_variant	Exon 1 of 2		XP_011534147.1
CALHM6	NM_001276460.2 link	c.10-921A>C		intron_variant	Intron 1 of 1		NP_001263389.1	Q5R3K3-2
CALHM6-AS1	NR_174951.1 link	n.87-1168T>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM6	ENST00000368605.3 link	c.433A>C	p.Ser145Arg	missense_variant	Exon 2 of 3	5	NM_001010919.3	ENSP00000357594.1		Q5R3K3-1
ENSG00000285446	ENST00000644499.1 link	c.767-921A>C		intron_variant	Intron 3 of 3			ENSP00000495266.1		A0A2R8Y6J1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000507

AC:

AN:

59122

Hom.:

AF XY:

0.0000287

AC XY:

AN XY:

34882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000143

AC:

186

AN:

1300318

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

639826

show subpopulations

Gnomad4 AFR exome

AF:

0.0000783

Gnomad4 AMR exome

AF:

0.0000473

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000146

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.0000747

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000469

Hom.:

Bravo

AF:

0.0000907

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.433A>C (p.S145R) alteration is located in exon 2 (coding exon 1) of the FAM26F gene. This alteration results from a A to C substitution at nucleotide position 433, causing the serine (S) at amino acid position 145 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

Benign

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.12

DANN

Benign

0.79

DEOGEN2

Benign

0.00089

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.25

M_CAP

Benign

0.0053

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.47

REVEL

Benign

0.022

Sift

Benign

0.53

Sift4G

Benign

0.56

Polyphen

0.0010

Vest4

0.080

MutPred

0.32

Gain of MoRF binding (P = 0.0651);

MVP

0.072

MPC

0.098

ClinPred

0.048

GERP RS

-9.7

Varity_R

0.10

gMVP

0.23

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