6-116461933-G-A

Variant names:

• chr6-116461933-G-A
• rs1407304430
• NM_001010919.3:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010919.3(CALHM6):​c.4G>A​(p.Glu2Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000053 in 1,508,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: CALHM6 NM_001010919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2773092).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010919.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM6	NM_001010919.3	MANE Select	c.4G>A	p.Glu2Lys	missense	Exon 2 of 3	NP_001010919.1	Q5R3K3-1
	CALHM6	NM_001276460.2		c.9+504G>A		intron	N/A	NP_001263389.1	Q5R3K3-2
	CALHM6-AS1	NR_174951.1		n.87-739C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM6	ENST00000368605.3	TSL:5 MANE Select	c.4G>A	p.Glu2Lys	missense	Exon 2 of 3	ENSP00000357594.1	Q5R3K3-1
	ENSG00000285446	ENST00000644499.1		c.767-1350G>A		intron	N/A	ENSP00000495266.1	A0A2R8Y6J1
	CALHM6	ENST00000859968.1		c.4G>A	p.Glu2Lys	missense	Exon 1 of 2	ENSP00000530027.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000516 AC: 7 AN: 1356260 Hom.: 0 Cov.: 33 AF XY: 0.00000603 AC XY: 4 AN XY: 663792

African (AFR) AF: 0.00 AC: 0 AN: 29726

American (AMR) AF: 0.00 AC: 0 AN: 32032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22898

East Asian (EAS) AF: 0.00 AC: 0 AN: 33944

South Asian (SAS) AF: 0.00 AC: 0 AN: 75352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 0.00000664 AC: 7 AN: 1053510

Other (OTH) AF: 0.00 AC: 0 AN: 55928

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.032	D
Polyphen		0.65	P
Vest4		0.093
MutPred		0.52		Gain of MoRF binding (P = 0)
MVP		0.55
MPC		0.21
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.11
gMVP		0.61
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs1407304430; hg19: chr6-116783096;