dbSNP rs1661553721: CNST:p.Leu43Val (chr1-246591689-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_152609.3(CNST):c.127C>G(p.Leu43Val) 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 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L43F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CNST
NM_152609.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.900

Variant links:

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]

CNST 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=0.1535219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNST	NM_152609.3 link	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 11	ENST00000366513.9	NP_689822.2	Q6PJW8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNST	ENST00000366513.9 link	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 11	1	NM_152609.3	ENSP00000355470.4	Q6PJW8-1
CNST	ENST00000366512.7 link	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 9	1		ENSP00000355469.3	Q6PJW8-2
CNST	ENST00000366511.1 link	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 4	3		ENSP00000355468.1	B1AQM9
CNST	ENST00000483271.1 link	n.398C>G		non_coding_transcript_exon_variant	Exon 2 of 8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727240

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.036

T;.;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;N;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.14

MutPred

0.47

Loss of stability (P = 0.1239);Loss of stability (P = 0.1239);Loss of stability (P = 0.1239);

MVP

0.18

MPC

0.22

ClinPred

0.90

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.079

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over