4-140392350-T-G

Position:

• chr4-140392350-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000325617.10(CLGN):​c.1520A>C​(p.Lys507Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLGN ENST00000325617.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21725234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLGN	NM_004362.3	c.1520A>C	p.Lys507Thr	missense_variant	13/15	ENST00000325617.10	NP_004353.1
CLGN	NM_001130675.2	c.1520A>C	p.Lys507Thr	missense_variant	14/16		NP_001124147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLGN	ENST00000325617.10	c.1520A>C	p.Lys507Thr	missense_variant	13/15	1	NM_004362.3	ENSP00000326699	P1
CLGN	ENST00000414773.5	c.1520A>C	p.Lys507Thr	missense_variant	14/16	1		ENSP00000392782	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 27, 2024

The c.1520A>C (p.K507T) 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 1520, causing the lysine (K) at amino acid position 507 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;D
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.69	T;.
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.0080	B;B
Vest4		0.28
MutPred		0.42		Loss of methylation at K507 (P = 0.0012);Loss of methylation at K507 (P = 0.0012);
MVP		0.69
MPC		0.12
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.32
gMVP		0.44

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: rs1728790336; hg19: chr4-141313504;