Variant 4-140392233-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004362.3(CLGN):c.1637A>C(p.Glu546Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CLGN
NM_004362.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

Variant links:

Genes affected

CLGN (HGNC:2060): (calmegin) Calmegin is a testis-specific endoplasmic reticulum chaperone protein. CLGN may play a role in spermatogeneisis and infertility. [provided by RefSeq, Jul 2008]

CLGN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17464578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLGN	NM_004362.3 linkuse as main transcript	c.1637A>C	p.Glu546Ala	missense_variant	13/15	ENST00000325617.10	NP_004353.1
CLGN	NM_001130675.2 linkuse as main transcript	c.1637A>C	p.Glu546Ala	missense_variant	14/16		NP_001124147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLGN	ENST00000325617.10 linkuse as main transcript	c.1637A>C	p.Glu546Ala	missense_variant	13/15	1	NM_004362.3	ENSP00000326699	P1	O14967-1
CLGN	ENST00000414773.5 linkuse as main transcript	c.1637A>C	p.Glu546Ala	missense_variant	14/16	1		ENSP00000392782	P1	O14967-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460392

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726524

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

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 10, 2023

The c.1637A>C (p.E546A) alteration is located in exon 14 (coding exon 12) of the CLGN gene. This alteration results from a A to C substitution at nucleotide position 1637, causing the glutamic acid (E) at amino acid position 546 to be replaced by an alanine (A). 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

0.097

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.19

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.12

Sift

Benign

0.17

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.91

P;P

Vest4

0.23

MutPred

0.22

Loss of glycosylation at K550 (P = 0.023);Loss of glycosylation at K550 (P = 0.023);

MVP

0.72

MPC

0.18

ClinPred

0.62

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.084

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