6-116558143-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001366078.2(CALHM4):c.877T>C(p.Phe293Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALHM4 NM_001366078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.638

Genes affected

CALHM4 (HGNC:21094): (calcium homeostasis modulator family member 4) 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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027470648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALHM4	NM_001366078.2	c.877T>C	p.Phe293Leu	missense_variant	2/2	ENST00000368596.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALHM4	ENST00000368596.4	c.877T>C	p.Phe293Leu	missense_variant	2/2	5	NM_001366078.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.319T>C (p.F107L) alteration is located in exon 3 (coding exon 1) of the FAM26D gene. This alteration results from a T to C substitution at nucleotide position 319, causing the phenylalanine (F) at amino acid position 107 to be replaced by a leucine (L). 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	11
Dann	Benign	0.66
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.63	T;T;T;T;T
Polyphen		0.0	.;.;.;.;B
Vest4		0.19
MutPred		0.28		.;.;.;.;Gain of disorder (P = 0.0658);
MVP		0.048
MPC		0.12
ClinPred		0.060	T
GERP RS		-1.3
Varity_R		0.037
gMVP		0.25

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.

Other links and lift over

hg19: chr6-116879306;