Variant 1-1917005-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_138705.4(CALML6):c.430A>G(p.Asn144Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000059 in 1,609,906 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 0.00033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CALML6
NM_138705.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

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=0.019102126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CALML6	NM_138705.4 linkuse as main transcript	c.430A>G	p.Asn144Asp	missense_variant	5/6	ENST00000307786.8	NP_619650.2
CALML6	NM_001330313.2 linkuse as main transcript	c.379A>G	p.Asn127Asp	missense_variant	4/5		NP_001317242.1
CALML6	XM_005244729.4 linkuse as main transcript	c.496A>G	p.Asn166Asp	missense_variant	5/6		XP_005244786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CALML6	ENST00000307786.8 linkuse as main transcript	c.430A>G	p.Asn144Asp	missense_variant	5/6	1	NM_138705.4	ENSP00000304643	P2
CALML6	ENST00000378604.3 linkuse as main transcript	c.379A>G	p.Asn127Asp	missense_variant	4/5	3		ENSP00000367867	A2
CALML6	ENST00000462293.1 linkuse as main transcript	n.504A>G		non_coding_transcript_exon_variant	3/3	3
CALML6	ENST00000482402.1 linkuse as main transcript	n.1663A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000766

AC:

AN:

247966

Hom.:

AF XY:

0.0000595

AC XY:

AN XY:

134428

show subpopulations

Gnomad AFR exome

AF:

0.000998

Gnomad AMR exome

AF:

0.0000873

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000309

AC:

AN:

1457694

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

724582

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000112

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.000328

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00116

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:

0.00

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.430A>G (p.N144D) alteration is located in exon 5 (coding exon 5) of the CALML6 gene. This alteration results from a A to G substitution at nucleotide position 430, causing the asparagine (N) at amino acid position 144 to be replaced by an aspartic acid (D). 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

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.064

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0086

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.085

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.078

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.041

D;D

Polyphen

0.0030

B;.

Vest4

0.14

MVP

0.20

MPC

0.052

ClinPred

0.018

GERP RS

-2.3

Varity_R

0.072

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over