6-116462075-T-C

Variant names:

• chr6-116462075-T-C
• rs938014565
• NM_001010919.3:c.146T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001010919.3(CALHM6):​c.146T>C​(p.Leu49Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CALHM6 NM_001010919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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]

ENSG00000285446 (HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM6	NM_001010919.3	c.146T>C	p.Leu49Pro	missense_variant	Exon 2 of 3	ENST00000368605.3	NP_001010919.1
CALHM6	XM_011535845.4	c.146T>C	p.Leu49Pro	missense_variant	Exon 1 of 2		XP_011534147.1
CALHM6	NM_001276460.2	c.9+646T>C		intron_variant	Intron 1 of 1		NP_001263389.1
CALHM6-AS1	NR_174951.1	n.87-881A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM6	ENST00000368605.3	c.146T>C	p.Leu49Pro	missense_variant	Exon 2 of 3	5	NM_001010919.3	ENSP00000357594.1
ENSG00000285446	ENST00000644499.1	c.767-1208T>C		intron_variant	Intron 3 of 3			ENSP00000495266.1
CALHM6	ENST00000368606.7	c.9+646T>C		intron_variant	Intron 1 of 1	3		ENSP00000357595.3
CALHM6-AS1	ENST00000476099.1	n.75-881A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395308 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 688300

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146T>C (p.L49P) alteration is located in exon 2 (coding exon 1) of the FAM26F gene. This alteration results from a T to C substitution at nucleotide position 146, causing the leucine (L) at amino acid position 49 to be replaced by a proline (P). 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	0.57
BayesDel_addAF	Benign	0.00029	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.24
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.67		Gain of catalytic residue at L49 (P = 0.0174);
MVP		0.43
MPC		0.60
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.80

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

Other links and lift over

dbSNP: rs938014565; hg19: chr6-116783238;