Genetic Variant NM_138705.4:c.433G>A (chr1-1917008-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_138705.4(CALML6):c.433G>A(p.Glu145Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,609,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. E145Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CALML6
NM_138705.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.03

Variant links:

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]

CALML6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3115965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALML6	NM_138705.4 link	c.433G>A	p.Glu145Lys	missense_variant	Exon 5 of 6	ENST00000307786.8	NP_619650.2	Q8TD86
CALML6	NM_001330313.2 link	c.382G>A	p.Glu128Lys	missense_variant	Exon 4 of 5		NP_001317242.1	B1AKR1
CALML6	XM_005244729.4 link	c.499G>A	p.Glu167Lys	missense_variant	Exon 5 of 6		XP_005244786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CALML6	ENST00000307786.8 link	c.433G>A	p.Glu145Lys	missense_variant	Exon 5 of 6	1	NM_138705.4	ENSP00000304643.3	Q8TD86
CALML6	ENST00000378604.3 link	c.382G>A	p.Glu128Lys	missense_variant	Exon 4 of 5	3		ENSP00000367867.3	B1AKR1
CALML6	ENST00000462293.1 link	n.507G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3
CALML6	ENST00000482402.1 link	n.1666G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247928

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1457644

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000721

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.075

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.23

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

1.0

D;.

Vest4

0.40

MutPred

0.50

Gain of methylation at E145 (P = 0.0071);.;

MVP

0.82

MPC

0.33

ClinPred

0.66

GERP RS

-0.43

Varity_R

0.095

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over