10-103458495-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001001412.4(CALHM1):c.257T>C(p.Leu86Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,612,874 control chromosomes in the GnomAD database, including 466,030 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.80 (49593 hom., cov: 33)
  • Exomes 𝑓: 0.75 (416437 hom.)
• Consequence: CALHM1 NM_001001412.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.156

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.984875E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALHM1	NM_001001412.4	c.257T>C	p.Leu86Pro	missense_variant	1/2	ENST00000329905.6
LOC124902494	XR_007062275.1	n.795-3935A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALHM1	ENST00000329905.6	c.257T>C	p.Leu86Pro	missense_variant	1/2	1	NM_001001412.4	P1
	ENST00000411906.1	n.392-3935A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.803 AC: 122013 AN: 152016 Hom.: 49542 Cov.: 33

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.888

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.782

GnomAD3 exomes AF: 0.789 AC: 195046 AN: 247100 Hom.: 77727 AF XY: 0.787 AC XY: 105950 AN XY: 134600

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.837

Gnomad ASJ exome AF: 0.740

Gnomad EAS exome AF: 0.884

Gnomad SAS exome AF: 0.865

Gnomad FIN exome AF: 0.792

Gnomad NFE exome AF: 0.724

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.753 AC: 1099252 AN: 1460740 Hom.: 416437 Cov.: 84 AF XY: 0.754 AC XY: 548004 AN XY: 726694

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.740

Gnomad4 EAS exome AF: 0.917

Gnomad4 SAS exome AF: 0.864

Gnomad4 FIN exome AF: 0.790

Gnomad4 NFE exome AF: 0.727

Gnomad4 OTH exome AF: 0.766

GnomAD4 genome AF: 0.803 AC: 122124 AN: 152134 Hom.: 49593 Cov.: 33 AF XY: 0.807 AC XY: 59990 AN XY: 74372

Gnomad4 AFR AF: 0.929

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.730

Gnomad4 EAS AF: 0.889

Gnomad4 SAS AF: 0.863

Gnomad4 FIN AF: 0.795

Gnomad4 NFE AF: 0.724

Gnomad4 OTH AF: 0.781

Alfa AF: 0.722 Hom.: 21848

Bravo AF: 0.809

TwinsUK AF: 0.725 AC: 2689

ALSPAC AF: 0.733 AC: 2825

ESP6500AA AF: 0.926 AC: 4077

ESP6500EA AF: 0.730 AC: 6271

ExAC AF: 0.784 AC: 94737

Asia WGS AF: 0.892 AC: 3104 AN: 3478

EpiCase AF: 0.723

EpiControl AF: 0.723

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	2.4
Dann	Benign	0.68
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.050	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.032
Sift	Benign	0.29	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.25
ClinPred		0.0024	T
GERP RS		1.4
Varity_R		0.053
gMVP		0.62

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: rs2986017; hg19: chr10-105218252; COSMIC: COSV61707262;