1-1916468-A-G

Position:

• chr1-1916468-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138705.4(CALML6):​c.106A>G​(p.Lys36Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALML6 NM_138705.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.126347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALML6	NM_138705.4	c.106A>G	p.Lys36Glu	missense_variant	3/6	ENST00000307786.8	NP_619650.2
CALML6	NM_001330313.2	c.55A>G	p.Lys19Glu	missense_variant	2/5		NP_001317242.1
CALML6	XM_005244729.4	c.172A>G	p.Lys58Glu	missense_variant	3/6		XP_005244786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALML6	ENST00000307786.8	c.106A>G	p.Lys36Glu	missense_variant	3/6	1	NM_138705.4	ENSP00000304643.3
CALML6	ENST00000378604.3	c.55A>G	p.Lys19Glu	missense_variant	2/5	3		ENSP00000367867.3
CALML6	ENST00000482402.1	n.1203A>G		non_coding_transcript_exon_variant	1/3	2
CALML6	ENST00000462293.1	n.328-284A>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

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

Dec 17, 2023

The c.106A>G (p.K36E) alteration is located in exon 3 (coding exon 3) of the CALML6 gene. This alteration results from a A to G substitution at nucleotide position 106, causing the lysine (K) at amino acid position 36 to be replaced by a glutamic acid (E). 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	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.046
Sift	Benign	0.048	D;D
Sift4G	Benign	0.88	T;T
Polyphen		0.73	P;.
Vest4		0.29
MutPred		0.36		Loss of ubiquitination at K36 (P = 0.0141);.;
MVP		0.51
MPC		0.062
ClinPred		0.11	T
GERP RS		1.1
Varity_R		0.098

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-1847907;