Genetic Variant CLDN34:p.His208Tyr (chrX-9967979-C-T) – 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.622C>T(p.His208Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000503 in 1,152,959 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.000034 ( 0 hom. 6 hem. )

Consequence

CLDN34
NM_001195081.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.360

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=0.010998666).

BS2

High Hemizygotes in GnomAd4 at 9 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.622C>T	p.His208Tyr	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.622C>T	p.His208Tyr	missense	Exon 1 of 1	ENSP00000403980.3	H7C241
ENSG00000310579	ENST00000850985.1		c.5227C>T	p.His1743Tyr	missense	Exon 10 of 10	ENSP00000521067.1
CLDN34	ENST00000850986.1		c.622C>T	p.His208Tyr	missense	Exon 2 of 2	ENSP00000521068.1

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

AN:

111966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000747

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

GnomAD2 exomes

AF:

0.0000512

AC:

AN:

97726

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000976

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1040938

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

339990

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

24903

American (AMR)

AF:

0.00

AC:

AN:

27903

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18627

East Asian (EAS)

AF:

0.00

AC:

AN:

27126

South Asian (SAS)

AF:

0.00

AC:

AN:

49855

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25904

Middle Eastern (MID)

AF:

0.000245

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

818262

Other (OTH)

AF:

0.000158

AC:

AN:

44274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000205

AC:

AN:

112021

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

AN XY:

34183

show subpopulations

African (AFR)

AF:

0.000745

AC:

AN:

30855

American (AMR)

AF:

0.00

AC:

AN:

10519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6107

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53273

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000545

Hom.:

Bravo

AF:

0.000219

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

0.070

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.6

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.0050

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.28

MetaRNN

Benign

0.011

PhyloP100

-0.36

PrimateAI

Benign

0.35

Sift4G

Benign

0.48

Vest4

0.053

MVP

0.048

GERP RS

-1.4

Varity_R

0.072

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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