NM_138694.4:c.4035C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_138694.4(PKHD1):c.4035C>A(p.Gly1345Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,186 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 16 hom., cov: 32)

Exomes 𝑓: 0.011 ( 193 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0430

Publications

2 publications found

Variant links:

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
polycystic kidney disease 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
Caroli disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 6-52025775-G-T is Benign according to our data. Variant chr6-52025775-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.043 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00859 (1309/152304) while in subpopulation SAS AF = 0.038 (183/4816). AF 95% confidence interval is 0.0335. There are 16 homozygotes in GnomAd4. There are 690 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. 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
	PKHD1	NM_138694.4	MANE Select	c.4035C>A	p.Gly1345Gly	synonymous	Exon 32 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.4035C>A	p.Gly1345Gly	synonymous	Exon 32 of 61	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.4035C>A	p.Gly1345Gly	synonymous	Exon 32 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.4035C>A	p.Gly1345Gly	synonymous	Exon 32 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.00860

AC:

1309

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.178

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.0380

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.0107

AC:

2693

AN:

251052

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00473

Gnomad FIN exome

AF:

0.00425

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00685

GnomAD4 exome

AF:

0.0114

AC:

16725

AN:

1461882

Hom.:

193

Cov.:

AF XY:

0.0122

AC XY:

8905

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

33480

American (AMR)

AF:

0.00297

AC:

133

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00386

AC:

101

AN:

26136

East Asian (EAS)

AF:

0.00179

AC:

AN:

39700

South Asian (SAS)

AF:

0.0360

AC:

3102

AN:

86258

European-Finnish (FIN)

AF:

0.00487

AC:

260

AN:

53418

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0112

AC:

12423

AN:

1112002

Other (OTH)

AF:

0.00924

AC:

558

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1064

2128

3192

4256

5320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.00859

AC:

1309

AN:

152304

Hom.:

Cov.:

AF XY:

0.00927

AC XY:

690

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41574

American (AMR)

AF:

0.00490

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00425

AC:

AN:

5180

South Asian (SAS)

AF:

0.0380

AC:

183

AN:

4816

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0106

AC:

722

AN:

68020

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

142

212

283

354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00787

Hom.:

Bravo

AF:

0.00839

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.00949

EpiControl

AF:

0.00919

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive polycystic kidney disease (3)

not provided (2)

not specified (2)

Polycystic kidney disease 4 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.79

(source)

DANN

Benign

0.24

PhyloP100

0.043

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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