6-116462359-C-G

Variant names:

• chr6-116462359-C-G
• rs534984948
• NM_001010919.3:c.430C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001010919.3(CALHM6):​c.430C>G​(p.Arg144Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,296,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: CALHM6 NM_001010919.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.345
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05788648).

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.430C>G	p.Arg144Gly	missense	Exon 2 of 3	NP_001010919.1	Q5R3K3-1
	CALHM6	NM_001276460.2		c.10-924C>G		intron	N/A	NP_001263389.1	Q5R3K3-2
	CALHM6-AS1	NR_174951.1		n.87-1165G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM6	ENST00000368605.3	TSL:5 MANE Select	c.430C>G	p.Arg144Gly	missense	Exon 2 of 3	ENSP00000357594.1	Q5R3K3-1
	ENSG00000285446	ENST00000644499.1		c.767-924C>G		intron	N/A	ENSP00000495266.1	A0A2R8Y6J1
	CALHM6	ENST00000859968.1		c.430C>G	p.Arg144Gly	missense	Exon 1 of 2	ENSP00000530027.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.71e-7 AC: 1 AN: 1296674 Hom.: 0 Cov.: 33 AF XY: 0.00000157 AC XY: 1 AN XY: 637794

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25482

American (AMR) AF: 0.00 AC: 0 AN: 20412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21280

East Asian (EAS) AF: 0.00 AC: 0 AN: 28254

South Asian (SAS) AF: 0.0000147 AC: 1 AN: 67846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3802

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038178

Other (OTH) AF: 0.00 AC: 0 AN: 53342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.39
DANN	Benign	0.64
DEOGEN2	Benign	0.00050	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.34
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.011
Sift	Benign	0.25	T
Sift4G	Benign	0.30	T
Polyphen		0.0050	B
Vest4		0.062
MutPred		0.38		Gain of loop (P = 0.024)
MVP		0.085
MPC		0.12
ClinPred		0.40	T
GERP RS		-9.4
PromoterAI		-0.011	Neutral
Varity_R		0.22
gMVP		0.22
Mutation Taster		=99/1	polymorphism

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: rs534984948; hg19: chr6-116783522;