Variant 14-95202850-C-T 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_024734.4(CLMN):c.2499G>A(p.Met833Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 1,533,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CLMN
NM_024734.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0800

Variant links:

Genes affected

CLMN (HGNC:19972): (calmin) Predicted to enable actin filament binding activity. Predicted to be involved in negative regulation of cell population proliferation and nuclear migration. Predicted to act upstream of or within neuron projection development. Predicted to be integral component of membrane. Predicted to be part of meiotic nuclear membrane microtubule tethering complex. Predicted to be active in cytoplasm and nuclear outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

CLMN links:

CLMN (HGNC:):

CLMN links:

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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=0.023997098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLMN	NM_024734.4 linkuse as main transcript	c.2499G>A	p.Met833Ile	missense_variant	9/13	ENST00000298912.9	NP_079010.2	Q96JQ2Q6NUQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLMN	ENST00000298912.9 linkuse as main transcript	c.2499G>A	p.Met833Ile	missense_variant	9/13	1	NM_024734.4	ENSP00000298912.3		Q96JQ2
CLMN	ENST00000556454.1 linkuse as main transcript	n.1863G>A		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

GnomAD3 exomes

AF:

0.0000645

AC:

AN:

185924

Hom.:

AF XY:

0.0000508

AC XY:

AN XY:

98460

show subpopulations

Gnomad AFR exome

AF:

0.000775

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000203

AC:

AN:

1381750

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

679886

show subpopulations

Gnomad4 AFR exome

AF:

0.000820

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:

0.00

Gnomad4 OTH exome

AF:

0.0000528

GnomAD4 genome

AF:

0.000223

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000796

Gnomad4 AMR

AF:

0.0000654

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:

0.00

Alfa

AF:

0.0000691

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000660

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

Jun 02, 2023

The c.2499G>A (p.M833I) alteration is located in exon 9 (coding exon 9) of the CLMN gene. This alteration results from a G to A substitution at nucleotide position 2499, causing the methionine (M) at amino acid position 833 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

0.13

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.2

DANN

Benign

0.80

DEOGEN2

Benign

0.029

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.36

M_CAP

Benign

0.075

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.20

PROVEAN

Benign

0.20

REVEL

Benign

0.20

Sift

Uncertain

0.0040

Sift4G

Benign

0.48

Polyphen

0.0040

Vest4

0.061

MutPred

0.047

Loss of glycosylation at K828 (P = 0.2443);

MVP

0.73

MPC

0.12

ClinPred

0.041

GERP RS

2.5

Varity_R

0.27

gMVP

0.064

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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