5-127657698-G-C

Position:

• chr5-127657698-G-C

Variant summary

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

The NM_001048252.3(CTXN3):​c.177G>C​(p.Met59Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTXN3 NM_001048252.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59

Genes affected

CTXN3 (HGNC:31110): (cortexin 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

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
CTXN3	NM_001048252.3	c.177G>C	p.Met59Ile	missense_variant	3/3	ENST00000379445.8	NP_001041717.1
LOC105379164	XR_002956226.1	n.140-5337C>G		intron_variant, non_coding_transcript_variant
CTXN3	NM_001127385.2	c.177G>C	p.Met59Ile	missense_variant	3/3		NP_001120857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTXN3	ENST00000379445.8	c.177G>C	p.Met59Ile	missense_variant	3/3	1	NM_001048252.3	ENSP00000368758	P1
CTXN3	ENST00000395322.3	c.177G>C	p.Met59Ile	missense_variant	3/3	1		ENSP00000378732	P1
	ENST00000512352.1	n.310-5337C>G		intron_variant, non_coding_transcript_variant		5
CTXN3	ENST00000620385.1	c.177G>C	p.Met59Ile	missense_variant	1/1			ENSP00000482081	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

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

Mar 20, 2023

The c.177G>C (p.M59I) alteration is located in exon 3 (coding exon 1) of the CTXN3 gene. This alteration results from a G to C substitution at nucleotide position 177, causing the methionine (M) at amino acid position 59 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.5	D;D;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.98	D;D;D
Vest4		0.69
MutPred		0.66		Loss of catalytic residue at M59 (P = 0.0542);Loss of catalytic residue at M59 (P = 0.0542);Loss of catalytic residue at M59 (P = 0.0542);
MVP		0.64
MPC		0.80
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.58

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: rs1288111980; hg19: chr5-126993390;