chr6-116512208-T-A

Variant names:

• chr6-116512208-T-A
• rs371671589
• NM_153711.5:c.512T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153711.5(CALHM5):​c.512T>A​(p.Leu171Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L171P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CALHM5 NM_153711.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.37
• Publications: 0 publications found

Genes affected

CALHM5 (HGNC:21568): (calcium homeostasis modulator family member 5) Predicted to enable cation channel activity. Predicted to be involved in cation transmembrane transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC3L (HGNC:21090): (trafficking protein particle complex subunit 3L) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport and intra-Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153711.5. 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
	CALHM5	NM_153711.5	MANE Select	c.512T>A	p.Leu171Gln	missense	Exon 1 of 2	NP_714922.1	Q8N5C1
	TRAPPC3L	NM_001139444.3	MANE Select	c.241-11542A>T		intron	N/A	NP_001132916.1	Q5T215-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM5	ENST00000368599.4	TSL:1 MANE Select	c.512T>A	p.Leu171Gln	missense	Exon 1 of 2	ENSP00000357588.3	Q8N5C1
	TRAPPC3L	ENST00000368602.4	TSL:5 MANE Select	c.241-11542A>T		intron	N/A	ENSP00000357591.3	Q5T215-1
	TRAPPC3L	ENST00000356128.4	TSL:2	c.-27A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000348445.4	Q5T215-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451998 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722326

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110932

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.0	T
PhyloP100		7.4
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.97	D
Vest4		0.73
MutPred		0.64		Loss of stability (P = 0.0173)
MVP		0.12
MPC		0.48
ClinPred		0.96	D
GERP RS		5.6
PromoterAI		0.16	Neutral
Varity_R		0.44
gMVP		0.58
Mutation Taster		=197/103	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371671589; hg19: chr6-116833371;