6-116462075-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001010919.3(CALHM6):​c.146T>G​(p.Leu49Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CALHM6 NM_001010919.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM6	NM_001010919.3	c.146T>G	p.Leu49Arg	missense_variant	Exon 2 of 3	ENST00000368605.3	NP_001010919.1
CALHM6	XM_011535845.4	c.146T>G	p.Leu49Arg	missense_variant	Exon 1 of 2		XP_011534147.1
CALHM6	NM_001276460.2	c.9+646T>G		intron_variant	Intron 1 of 1		NP_001263389.1
CALHM6-AS1	NR_174951.1	n.87-881A>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM6	ENST00000368605.3	c.146T>G	p.Leu49Arg	missense_variant	Exon 2 of 3	5	NM_001010919.3	ENSP00000357594.1
ENSG00000285446	ENST00000644499.1	c.767-1208T>G		intron_variant	Intron 3 of 3			ENSP00000495266.1
CALHM6	ENST00000368606.7	c.9+646T>G		intron_variant	Intron 1 of 1	3		ENSP00000357595.3
CALHM6-AS1	ENST00000476099.1	n.75-881A>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.23
Sift	Benign	0.033	D
Sift4G	Uncertain	0.025	D
Polyphen		0.99	D
Vest4		0.60
MutPred		0.67		Loss of stability (P = 0.046);
MVP		0.44
MPC		0.57
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.39
gMVP		0.62

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;