Genetic Variant NM_001195081.2:c.13T>G (chrX-9967370-T-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001195081.2(CLDN34):c.13T>G(p.Cys5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,150,247 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.00018 ( 0 hom. 78 hem. )

Consequence

CLDN34
NM_001195081.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.26

Publications

0 publications found

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:

ENSG00000310579 (HGNC:):

ENSG00000310579 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05162996).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195081.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN34	NM_001195081.2	MANE Select	c.13T>G	p.Cys5Gly	missense	Exon 1 of 1	NP_001182010.1	H7C241

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN34	ENST00000445307.4	TSL:6 MANE Select	c.13T>G	p.Cys5Gly	missense	Exon 1 of 1	ENSP00000403980.3	H7C241
ENSG00000310579	ENST00000850985.1		c.4618T>G	p.Cys1540Gly	missense	Exon 10 of 10	ENSP00000521067.1
CLDN34	ENST00000850986.1		c.13T>G	p.Cys5Gly	missense	Exon 2 of 2	ENSP00000521068.1

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

111652

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.000207

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000626

AC:

AN:

95884

AF XY:

0.000144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000181

AC:

188

AN:

1038595

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

AN XY:

338167

show subpopulations

African (AFR)

AF:

0.0000403

AC:

AN:

24841

American (AMR)

AF:

0.0000360

AC:

AN:

27784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18527

East Asian (EAS)

AF:

0.00

AC:

AN:

27040

South Asian (SAS)

AF:

0.00

AC:

AN:

49724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4071

European-Non Finnish (NFE)

AF:

0.000223

AC:

182

AN:

816605

Other (OTH)

AF:

0.0000906

AC:

AN:

44139

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000107

AC:

AN:

111652

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33820

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30713

American (AMR)

AF:

0.00

AC:

AN:

10465

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00

AC:

AN:

2683

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000207

AC:

AN:

53110

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000531

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.032

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.013

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.21

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.1

PhyloP100

-1.3

PrimateAI

Benign

0.35

REVEL

Benign

0.025

Sift4G

Uncertain

0.058

Vest4

0.097

MVP

0.17

ClinPred

0.027

GERP RS

-7.0

PromoterAI

0.019

Neutral

(source)

Varity_R

0.085

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over