chr6-116557987-C-T

Variant names:

• chr6-116557987-C-T
• rs771019537
• NM_001366078.2:c.721C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366078.2(CALHM4):​c.721C>T​(p.Arg241Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CALHM4 NM_001366078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.230
• Publications: 2 publications found

Genes affected

CALHM4 (HGNC:21094): (calcium homeostasis modulator family member 4) 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10027486).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366078.2. 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
	CALHM4	NM_001366078.2	MANE Select	c.721C>T	p.Arg241Trp	missense	Exon 2 of 2	NP_001353007.1	Q5JW98-1
	CALHM4	NM_001256887.3		c.292C>T	p.Arg98Trp	missense	Exon 4 of 4	NP_001243816.1	Q5JW98-3
	CALHM4	NM_001256888.3		c.289C>T	p.Arg97Trp	missense	Exon 4 of 4	NP_001243817.1	Q5JW98-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM4	ENST00000368596.4	TSL:5 MANE Select	c.721C>T	p.Arg241Trp	missense	Exon 2 of 2	ENSP00000357585.3	Q5JW98-1
	CALHM4	ENST00000405399.5	TSL:1	c.292C>T	p.Arg98Trp	missense	Exon 4 of 4	ENSP00000385836.1	Q5JW98-3
	CALHM4	ENST00000368597.6	TSL:1	c.163C>T	p.Arg55Trp	missense	Exon 3 of 3	ENSP00000357586.2	Q5JW98-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251432 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111996

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000826 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

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	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.23
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.10
Sift	Benign	0.045	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.038	B
Vest4		0.36
MVP		0.11
MPC		0.12
ClinPred		0.40	T
GERP RS		0.60
Varity_R		0.29
gMVP		0.31
Mutation Taster		=86/14	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: rs771019537; hg19: chr6-116879150;