Genetic Variant CALHM6:p.Thr79Ile (chr6-116462165-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001010919.3(CALHM6):c.236C>T(p.Thr79Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000728 in 1,374,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

CALHM6
NM_001010919.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.97

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM6	NM_001010919.3 link	c.236C>T	p.Thr79Ile	missense_variant	Exon 2 of 3	ENST00000368605.3	NP_001010919.1	Q5R3K3-1
CALHM6	XM_011535845.4 link	c.236C>T	p.Thr79Ile	missense_variant	Exon 1 of 2		XP_011534147.1
CALHM6	NM_001276460.2 link	c.9+736C>T		intron_variant	Intron 1 of 1		NP_001263389.1	Q5R3K3-2
CALHM6-AS1	NR_174951.1 link	n.87-971G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CALHM6	ENST00000368605.3 link	c.236C>T	p.Thr79Ile	missense_variant	Exon 2 of 3	5	NM_001010919.3	ENSP00000357594.1	Q5R3K3-1
ENSG00000285446	ENST00000644499.1 link	c.767-1118C>T		intron_variant	Intron 3 of 3			ENSP00000495266.1	A0A2R8Y6J1
CALHM6	ENST00000368606.7 link	c.9+736C>T		intron_variant	Intron 1 of 1	3		ENSP00000357595.3	Q5R3K3-2
CALHM6-AS1	ENST00000476099.1 link	n.75-971G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.28e-7

AC:

AN:

1374114

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

677828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000403

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

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

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236C>T (p.T79I) alteration is located in exon 2 (coding exon 1) of the FAM26F gene. This alteration results from a C to T substitution at nucleotide position 236, causing the threonine (T) at amino acid position 79 to be replaced by an isoleucine (I). 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

0.81

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.92

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.4

REVEL

Uncertain

0.33

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.56

MutPred

0.72

Loss of loop (P = 0.0804);

MVP

0.58

MPC

0.49

ClinPred

1.0

GERP RS

5.1

Varity_R

0.57

gMVP

0.74

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

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