1-1916793-G-A

Position:

• chr1-1916793-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138705.4(CALML6):​c.295G>A​(p.Gly99Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CALML6 NM_138705.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

Genes affected

CALML6 (HGNC:24193): (calmodulin like 6) Predicted to enable calcium ion binding activity and enzyme regulator activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALML6	NM_138705.4	c.295G>A	p.Gly99Arg	missense_variant	4/6	ENST00000307786.8	NP_619650.2
CALML6	NM_001330313.2	c.244G>A	p.Gly82Arg	missense_variant	3/5		NP_001317242.1
CALML6	XM_005244729.4	c.361G>A	p.Gly121Arg	missense_variant	4/6		XP_005244786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALML6	ENST00000307786.8	c.295G>A	p.Gly99Arg	missense_variant	4/6	1	NM_138705.4	ENSP00000304643	P2
CALML6	ENST00000378604.3	c.244G>A	p.Gly82Arg	missense_variant	3/5	3		ENSP00000367867	A2
CALML6	ENST00000462293.1	n.369G>A		non_coding_transcript_exon_variant	2/3	3
CALML6	ENST00000482402.1	n.1528G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2024

The c.295G>A (p.G99R) alteration is located in exon 4 (coding exon 4) of the CALML6 gene. This alteration results from a G to A substitution at nucleotide position 295, causing the glycine (G) at amino acid position 99 to be replaced by an arginine (R). 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	0.59
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.78	N;.
MutationTaster	Benign	0.85	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.055	T;T
Polyphen		0.98	D;.
Vest4		0.69
MutPred		0.49		Loss of catalytic residue at V100 (P = 0.0334);.;
MVP		0.61
MPC		0.33
ClinPred		0.76	D
GERP RS		2.0
Varity_R		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1848232;