1-246621552-T-G

Variant names:

• chr1-246621552-T-G
• rs532230816
• NM_152609.3:c.503T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152609.3(CNST):​c.503T>G​(p.Leu168Arg) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L168P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNST NM_152609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0570
• Publications: 0 publications found

Genes affected

CNST (HGNC:26486): (consortin, connexin sorting protein) Targeting of numerous transmembrane proteins to the cell surface is thought to depend on their recognition by cargo receptors that interact with the adaptor machinery for anterograde traffic at the distal end of the Golgi complex. Consortin (CNST) is an integral membrane protein that acts as a binding partner of connexins, the building blocks of gap junctions, and acts as a trans-Golgi network (TGN) receptor involved in connexin targeting to the plasma membrane and recycling from the cell surface (del Castillo et al., 2010 [PubMed 19864490]).[supplied by OMIM, Jun 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06611544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNST	NM_152609.3	c.503T>G	p.Leu168Arg	missense_variant	Exon 3 of 11	ENST00000366513.9	NP_689822.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNST	ENST00000366513.9	c.503T>G	p.Leu168Arg	missense_variant	Exon 3 of 11	1	NM_152609.3	ENSP00000355470.4
CNST	ENST00000366512.7	c.503T>G	p.Leu168Arg	missense_variant	Exon 3 of 9	1		ENSP00000355469.3
CNST	ENST00000483271.1	n.774T>G		non_coding_transcript_exon_variant	Exon 3 of 8	2
CNST	ENST00000366511.1	c.380-10342T>G		intron_variant	Intron 2 of 3	3		ENSP00000355468.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.2
DANN	Benign	0.96
DEOGEN2	Benign	0.0050	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		-0.057
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.034
Sift	Benign	0.39	T;T
Sift4G	Benign	0.081	T;D
Polyphen		0.0090	B;B
Vest4		0.18
MutPred		0.31		Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);
MVP		0.24
MPC		0.12
ClinPred		0.077	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.10
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs532230816; hg19: chr1-246784854;