NM_138694.4:c.1694-32C>G

Variant names:

• chr6-52055761-G-C
• rs12196276
• NM_138694.4:c.1694-32C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.1694-32C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,609,904 control chromosomes in the GnomAD database, including 1,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (78 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1271 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.608
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-52055761-G-C is Benign according to our data. Variant chr6-52055761-G-C is described in ClinVar as Benign. ClinVar VariationId is 262390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.1694-32C>G		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.1694-32C>G		intron	N/A	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.1694-32C>G		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.1694-32C>G		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3903 AN: 152142 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00678

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0331 AC: 8217 AN: 248304 AF XY: 0.0363

Gnomad AFR exome AF: 0.00559

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.00489

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0386

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0366 AC: 53293 AN: 1457644 Hom.: 1271 Cov.: 30 AF XY: 0.0381 AC XY: 27659 AN XY: 725190

African (AFR) AF: 0.00539 AC: 180 AN: 33398

American (AMR) AF: 0.0154 AC: 685 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 552 AN: 26080

East Asian (EAS) AF: 0.00192 AC: 76 AN: 39664

South Asian (SAS) AF: 0.0832 AC: 7151 AN: 85930

European-Finnish (FIN) AF: 0.0145 AC: 772 AN: 53208

Middle Eastern (MID) AF: 0.0350 AC: 195 AN: 5570

European-Non Finnish (NFE) AF: 0.0378 AC: 41869 AN: 1108994

Other (OTH) AF: 0.0301 AC: 1813 AN: 60226

GnomAD4 genome AF: 0.0257 AC: 3907 AN: 152260 Hom.: 78 Cov.: 32 AF XY: 0.0259 AC XY: 1930 AN XY: 74454

African (AFR) AF: 0.00676 AC: 281 AN: 41550

American (AMR) AF: 0.0157 AC: 240 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3470

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5180

South Asian (SAS) AF: 0.0833 AC: 401 AN: 4816

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10618

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2545 AN: 68006

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0180 Hom.: 11

Bravo AF: 0.0251

Asia WGS AF: 0.0420 AC: 148 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive polycystic kidney disease Benign:1

Apr 13, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Jul 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polycystic kidney disease 4 Benign:1

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.45
DANN	Benign	0.36
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12196276; hg19: chr6-51920559; COSMIC: COSV107435525;