10-103455334-C-T

Variant names:

• chr10-103455334-C-T
• rs41287500
• NM_001001412.4:c.969G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001001412.4(CALHM1):​c.969G>A​(p.Met323Ile) 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 1,613,582 control chromosomes in the GnomAD database, including 446 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.017 (21 hom., cov: 34)
  • Exomes 𝑓: 0.022 (425 hom.)
• Consequence: CALHM1 NM_001001412.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.275
• Publications: 9 publications found

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]

ENSG00000234699 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028559566).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2522/152380) while in subpopulation NFE AF = 0.0253 (1721/68040). AF 95% confidence interval is 0.0243. There are 21 homozygotes in GnomAd4. There are 1162 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001412.4. 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
	CALHM1	NM_001001412.4	MANE Select	c.969G>A	p.Met323Ile	missense	Exon 2 of 2	NP_001001412.3	Q8IU99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM1	ENST00000329905.6	TSL:1 MANE Select	c.969G>A	p.Met323Ile	missense	Exon 2 of 2	ENSP00000329926.6	Q8IU99
	ENSG00000234699	ENST00000411906.2	TSL:2	n.1170+2098C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2520 AN: 152262 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0160 AC: 4000 AN: 249428 AF XY: 0.0159

Gnomad AFR exome AF: 0.00623

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00860

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0223 AC: 32545 AN: 1461202 Hom.: 425 Cov.: 35 AF XY: 0.0218 AC XY: 15820 AN XY: 726944

African (AFR) AF: 0.00606 AC: 203 AN: 33478

American (AMR) AF: 0.0112 AC: 501 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00724 AC: 189 AN: 26116

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00943 AC: 813 AN: 86230

European-Finnish (FIN) AF: 0.0149 AC: 790 AN: 52882

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5768

European-Non Finnish (NFE) AF: 0.0259 AC: 28745 AN: 1111944

Other (OTH) AF: 0.0203 AC: 1227 AN: 60376

GnomAD4 genome AF: 0.0166 AC: 2522 AN: 152380 Hom.: 21 Cov.: 34 AF XY: 0.0156 AC XY: 1162 AN XY: 74522

African (AFR) AF: 0.00702 AC: 292 AN: 41592

American (AMR) AF: 0.0133 AC: 204 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4832

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10628

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1721 AN: 68040

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0218 Hom.: 136

Bravo AF: 0.0153

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0169 AC: 2049

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0240

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.28
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.019
MutPred		0.30		Loss of disorder (P = 0.0511)
MPC		0.17
ClinPred		0.0042	T
GERP RS		3.7
Varity_R		0.22
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs41287500; hg19: chr10-105215091; COSMIC: COSV107291560;