Genetic Variant NM_001001412.4:c.353C>A (chr10-103458399-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001001412.4(CALHM1):c.353C>A(p.Thr118Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CALHM1
NM_001001412.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.35

Variant links:

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]

CALHM1 links:

ENSG00000234699 (HGNC:):

ENSG00000234699 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM1	NM_001001412.4 link	c.353C>A	p.Thr118Lys	missense_variant	Exon 1 of 2	ENST00000329905.6	NP_001001412.3	Q8IU99
LOC124902494	XR_007062275.1 link	n.795-4031G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM1	ENST00000329905.6 link	c.353C>A	p.Thr118Lys	missense_variant	Exon 1 of 2	1	NM_001001412.4	ENSP00000329926.6		Q8IU99
ENSG00000234699	ENST00000411906.1 link	n.392-4031G>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1456668

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

723862

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.353C>A (p.T118K) alteration is located in exon 1 (coding exon 1) of the CALHM1 gene. This alteration results from a C to A substitution at nucleotide position 353, causing the threonine (T) at amino acid position 118 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.95

MVP

0.31

MPC

0.74

ClinPred

0.99

GERP RS

5.5

Varity_R

0.75

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over