rs41287502

Positions:

• chr10-103455459-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000329905.6(CALHM1):​c.844G>T​(p.Gly282Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,613,672 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (21 hom., cov: 34)
  • Exomes 𝑓: 0.022 (425 hom.)
• Consequence: CALHM1 ENST00000329905.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385

Genes affected

CALHM1 (HGNC:23494): (calcium homeostasis modulator 1) This gene encodes a calcium channel that plays a role in processing of amyloid-beta precursor protein. A polymorphism at this locus has been reported to be associated with susceptibility to late-onset Alzheimer's disease in some populations, but the pathogenicity of this polymorphism is unclear.[provided by RefSeq, Mar 2010]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029388368).
• BP6: Variant 10-103455459-C-A is Benign according to our data. Variant chr10-103455459-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2524/152358) while in subpopulation NFE AF= 0.0253 (1722/68028). AF 95% confidence interval is 0.0243. There are 21 homozygotes in gnomad4. There are 1163 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALHM1	NM_001001412.4	c.844G>T	p.Gly282Cys	missense_variant	2/2	ENST00000329905.6	NP_001001412.3
LOC124902494	XR_007062275.1	n.794+2223C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALHM1	ENST00000329905.6	c.844G>T	p.Gly282Cys	missense_variant	2/2	1	NM_001001412.4	ENSP00000329926	P1
	ENST00000411906.1	n.391+2223C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2522 AN: 152240 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.00704

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0162 AC: 4032 AN: 249582 Hom.: 43 AF XY: 0.0160 AC XY: 2166 AN XY: 135218

Gnomad AFR exome AF: 0.00642

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00871

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00999

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0223 AC: 32553 AN: 1461314 Hom.: 425 Cov.: 35 AF XY: 0.0218 AC XY: 15825 AN XY: 726982

Gnomad4 AFR exome AF: 0.00606

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00956

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0259

Gnomad4 OTH exome AF: 0.0203

GnomAD4 genome AF: 0.0166 AC: 2524 AN: 152358 Hom.: 21 Cov.: 34 AF XY: 0.0156 AC XY: 1163 AN XY: 74504

Gnomad4 AFR AF: 0.00705

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0204 Hom.: 17

Bravo AF: 0.0153

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0210 AC: 181

ExAC AF: 0.0170 AC: 2064

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0239

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.048
Sift	Benign	0.085	T
Sift4G	Benign	0.088	T
Polyphen		0.33	B
Vest4		0.075
MPC		0.30
ClinPred		0.0054	T
GERP RS		-0.98
Varity_R		0.096
gMVP		0.35

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: rs41287502; hg19: chr10-105215216; COSMIC: COSV53298132; COSMIC: COSV53298132;