6-116511994-C-G

Variant names:

• chr6-116511994-C-G
• NM_153711.5:c.298C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153711.5(CALHM5):​c.298C>G​(p.Leu100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CALHM5 NM_153711.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2974296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM5	NM_153711.5	c.298C>G	p.Leu100Val	missense_variant	Exon 1 of 2	ENST00000368599.4	NP_714922.1
TRAPPC3L	NM_001139444.3	c.241-11328G>C		intron_variant	Intron 3 of 4	ENST00000368602.4	NP_001132916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM5	ENST00000368599.4	c.298C>G	p.Leu100Val	missense_variant	Exon 1 of 2	1	NM_153711.5	ENSP00000357588.3
TRAPPC3L	ENST00000368602.4	c.241-11328G>C		intron_variant	Intron 3 of 4	5	NM_001139444.3	ENSP00000357591.3
TRAPPC3L	ENST00000437098.5	c.199-11328G>C		intron_variant	Intron 2 of 3	3		ENSP00000395769.1
TRAPPC3L	ENST00000356128.4	c.-13+200G>C		intron_variant	Intron 1 of 2	2		ENSP00000348445.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.298C>G (p.L100V) alteration is located in exon 1 (coding exon 1) of the FAM26E gene. This alteration results from a C to G substitution at nucleotide position 298, causing the leucine (L) at amino acid position 100 to be replaced by a valine (V). 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	0.096
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.077
Sift	Benign	0.043	D
Sift4G	Benign	0.077	T
Polyphen		0.93	P
Vest4		0.43
MutPred		0.67		Gain of sheet (P = 0.0477);
MVP		0.030
MPC		0.16
ClinPred		0.70	D
GERP RS		2.3
Varity_R		0.099
gMVP		0.47

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: chr6-116833157;