Genetic Variant CLDN34:p.Gly205Ser (chrX-9967970-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001195081.2(CLDN34):c.613G>A(p.Gly205Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000607 in 1,152,663 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000058 ( 0 hom. 2 hem. )

Consequence

CLDN34
NM_001195081.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.57

Variant links:

Genes affected

CLDN34 (HGNC:51259): (claudin 34) Predicted to enable structural molecule activity. Predicted to be involved in bicellular tight junction assembly and cell adhesion. Predicted to be integral component of membrane. Predicted to be active in bicellular tight junction and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CLDN34 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN34	NM_001195081.2 link	c.613G>A	p.Gly205Ser	missense_variant	Exon 1 of 1	ENST00000445307.4	NP_001182010.1	H7C241

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN34	ENST00000445307.4 link	c.613G>A	p.Gly205Ser	missense_variant	Exon 1 of 1	6	NM_001195081.2	ENSP00000403980.3		H7C241

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111813

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33981

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000307

AC:

AN:

97772

Hom.:

AF XY:

0.0000274

AC XY:

AN XY:

36514

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000576

AC:

AN:

1040850

Hom.:

Cov.:

AF XY:

0.00000588

AC XY:

AN XY:

339912

show subpopulations

Gnomad4 AFR exome

AF:

0.0000402

Gnomad4 AMR exome

AF:

0.000108

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:

0.00000244

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111813

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33981

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.613G>A (p.G205S) alteration is located in exon 1 (coding exon 1) of the CLDN34 gene. This alteration results from a G to A substitution at nucleotide position 613, causing the glycine (G) at amino acid position 205 to be replaced by a serine (S). 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

0.075

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.25

DANN

Benign

0.37

DEOGEN2

Benign

0.0022

FATHMM_MKL

Benign

0.00084

LIST_S2

Benign

0.26

MetaRNN

Benign

0.043

PrimateAI

Benign

0.24

Sift4G

Benign

0.75

Vest4

0.076

MVP

0.13

GERP RS

-6.4

Varity_R

0.038

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over