chr10-103458295-C-T

Position:

• chr10-103458295-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001001412.4(CALHM1):​c.457G>A​(p.Ala153Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,611,950 control chromosomes in the GnomAD database, including 34 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 ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (18 hom.)
• Consequence: CALHM1 NM_001001412.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.115

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020844638).
• BP6: Variant 10-103458295-C-T is Benign according to our data. Variant chr10-103458295-C-T is described in ClinVar as [Benign]. Clinvar id is 781217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00852 (1298/152326) while in subpopulation AFR AF= 0.0279 (1161/41568). AF 95% confidence interval is 0.0266. There are 16 homozygotes in gnomad4. There are 627 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALHM1	NM_001001412.4	c.457G>A	p.Ala153Thr	missense_variant	1/2	ENST00000329905.6	NP_001001412.3
LOC124902494	XR_007062275.1	n.795-4135C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALHM1	ENST00000329905.6	c.457G>A	p.Ala153Thr	missense_variant	1/2	1	NM_001001412.4	ENSP00000329926.6
ENSG00000234699	ENST00000411906.1	n.392-4135C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00851 AC: 1295 AN: 152208 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00276 AC: 666 AN: 241274 Hom.: 6 AF XY: 0.00217 AC XY: 286 AN XY: 131740

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00120 AC: 1747 AN: 1459624 Hom.: 18 Cov.: 31 AF XY: 0.00108 AC XY: 783 AN XY: 726142

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00985

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00852 AC: 1298 AN: 152326 Hom.: 16 Cov.: 33 AF XY: 0.00842 AC XY: 627 AN XY: 74498

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00371 Hom.: 2

Bravo AF: 0.00964

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000933 AC: 8

ExAC AF: 0.00302 AC: 365

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 02, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.058
Sift	Benign	0.58	T
Sift4G	Benign	0.58	T
Polyphen		0.0080	B
Vest4		0.051
MVP		0.030
MPC		0.15
ClinPred		0.0027	T
GERP RS		3.6
Varity_R		0.046
gMVP		0.44

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: rs114710405; hg19: chr10-105218052;