Genetic Variant NM_138705.4:c.139G>A (chr1-1916501-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138705.4(CALML6):c.139G>A(p.Glu47Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,596,340 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

CALML6
NM_138705.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.423

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01820314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALML6	NM_138705.4 link	c.139G>A	p.Glu47Lys	missense_variant	Exon 3 of 6	ENST00000307786.8	NP_619650.2	Q8TD86
CALML6	NM_001330313.2 link	c.88G>A	p.Glu30Lys	missense_variant	Exon 2 of 5		NP_001317242.1	B1AKR1
CALML6	XM_005244729.4 link	c.205G>A	p.Glu69Lys	missense_variant	Exon 3 of 6		XP_005244786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CALML6	ENST00000307786.8 link	c.139G>A	p.Glu47Lys	missense_variant	Exon 3 of 6	1	NM_138705.4	ENSP00000304643.3	Q8TD86
CALML6	ENST00000378604.3 link	c.88G>A	p.Glu30Lys	missense_variant	Exon 2 of 5	3		ENSP00000367867.3	B1AKR1
CALML6	ENST00000482402.1 link	n.1236G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
CALML6	ENST00000462293.1 link	n.328-251G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000544

AC:

AN:

220604

Hom.:

AF XY:

0.0000587

AC XY:

AN XY:

119298

show subpopulations

Gnomad AFR exome

AF:

0.000739

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:

0.0000102

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.0000457

AC:

AN:

1444004

Hom.:

Cov.:

AF XY:

0.0000488

AC XY:

AN XY:

716944

show subpopulations

Gnomad4 AFR exome

AF:

0.000729

Gnomad4 AMR exome

AF:

0.0000244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000236

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.000210

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000746

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000447

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000578

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139G>A (p.E47K) alteration is located in exon 3 (coding exon 3) of the CALML6 gene. This alteration results from a G to A substitution at nucleotide position 139, causing the glutamic acid (E) at amino acid position 47 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

Benign

0.095

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0093

T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

1.7

N;N

REVEL

Benign

0.095

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

1.0

D;.

Vest4

0.21

MVP

0.54

MPC

0.23

ClinPred

0.060

GERP RS

0.28

Varity_R

0.068

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