dbSNP rs368720866: CALML6:p.Val41Ile (chr1-1916483-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.121G>A(p.Val41Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,572,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

CALML6
NM_138705.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

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=0.013502151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALML6	NM_138705.4 link	c.121G>A	p.Val41Ile	missense_variant	Exon 3 of 6	ENST00000307786.8	NP_619650.2	Q8TD86
CALML6	NM_001330313.2 link	c.70G>A	p.Val24Ile	missense_variant	Exon 2 of 5		NP_001317242.1	B1AKR1
CALML6	XM_005244729.4 link	c.187G>A	p.Val63Ile	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.121G>A	p.Val41Ile	missense_variant	Exon 3 of 6	1	NM_138705.4	ENSP00000304643.3	Q8TD86
CALML6	ENST00000378604.3 link	c.70G>A	p.Val24Ile	missense_variant	Exon 2 of 5	3		ENSP00000367867.3	B1AKR1
CALML6	ENST00000482402.1 link	n.1218G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
CALML6	ENST00000462293.1 link	n.328-269G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

187200

Hom.:

AF XY:

0.0000997

AC XY:

AN XY:

100338

show subpopulations

Gnomad AFR exome

AF:

0.000363

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000901

Gnomad SAS exome

AF:

0.0000782

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000600

GnomAD4 exome

AF:

0.0000422

AC:

AN:

1420602

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

703288

show subpopulations

Gnomad4 AFR exome

AF:

0.000124

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000404

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.000645

GnomAD4 genome

AF:

0.000118

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121G>A (p.V41I) 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 121, causing the valine (V) at amino acid position 41 to be replaced by an isoleucine (I). 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

-0.56

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.57

N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.62

N;N

REVEL

Benign

0.058

Sift

Benign

0.056

T;T

Sift4G

Benign

0.088

T;T

Polyphen

0.0020

B;.

Vest4

0.18

MVP

0.32

MPC

0.043

ClinPred

0.0090

GERP RS

0.36

Varity_R

0.063

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

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