NM_138694.4:c.8441-2295G>A

Variant names:

• chr6-51778216-C-T
• rs728996
• NM_138694.4:c.8441-2295G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138694.4(PKHD1):​c.8441-2295G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 151,936 control chromosomes in the GnomAD database, including 25,914 homozygotes. 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 0.57 (25914 hom., cov: 32)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.808 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.8441-2295G>A		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8441-2295G>A		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.8441-2295G>A		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.8441-2295G>A		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86868 AN: 151818 Hom.: 25918 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.567

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.572 AC: 86882 AN: 151936 Hom.: 25914 Cov.: 32 AF XY: 0.580 AC XY: 43046 AN XY: 74228

African (AFR) AF: 0.404 AC: 16759 AN: 41452

American (AMR) AF: 0.654 AC: 9954 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1884 AN: 3466

East Asian (EAS) AF: 0.829 AC: 4277 AN: 5160

South Asian (SAS) AF: 0.739 AC: 3565 AN: 4824

European-Finnish (FIN) AF: 0.637 AC: 6717 AN: 10540

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41933 AN: 67952

Other (OTH) AF: 0.566 AC: 1196 AN: 2112

Alfa AF: 0.594 Hom.: 41856

Bravo AF: 0.561

Asia WGS AF: 0.724 AC: 2517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0040
DANN	Benign	0.60
PhyloP100		-2.2
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: rs728996; hg19: chr6-51643014;