4-140396120-C-T

Position:

• chr4-140396120-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000325617.10(CLGN):​c.970G>A​(p.Asp324Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D324H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CLGN ENST00000325617.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLGN	NM_004362.3	c.970G>A	p.Asp324Asn	missense_variant	9/15	ENST00000325617.10	NP_004353.1
CLGN	NM_001130675.2	c.970G>A	p.Asp324Asn	missense_variant	10/16		NP_001124147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLGN	ENST00000325617.10	c.970G>A	p.Asp324Asn	missense_variant	9/15	1	NM_004362.3	ENSP00000326699	P1
CLGN	ENST00000414773.5	c.970G>A	p.Asp324Asn	missense_variant	10/16	1		ENSP00000392782	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.970G>A (p.D324N) alteration is located in exon 10 (coding exon 8) of the CLGN gene. This alteration results from a G to A substitution at nucleotide position 970, causing the aspartic acid (D) at amino acid position 324 to be replaced by an asparagine (N). 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	0.080
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.12
Sift	Benign	0.23	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.11	B;B
Vest4		0.26
MutPred		0.86		Loss of glycosylation at K320 (P = 0.0217);Loss of glycosylation at K320 (P = 0.0217);
MVP		0.60
MPC		0.14
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.25
gMVP		0.60

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

Other links and lift over

dbSNP: rs868506790; hg19: chr4-141317274;