6-51657690-G-C

Variant names:

• chr6-51657690-G-C
• rs1414503
• NM_138694.4:c.11174+1262C>G

Variant summary

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

The NM_138694.4(PKHD1):​c.11174+1262C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 151,962 control chromosomes in the GnomAD database, including 4,376 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 0.21 (4376 hom., cov: 32)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 3 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124900615 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.11174+1262C>G		intron	N/A	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.11174+1262C>G		intron	N/A	ENSP00000360158.3	P08F94-1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32333 AN: 151844 Hom.: 4374 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.213 AC: 32361 AN: 151962 Hom.: 4376 Cov.: 32 AF XY: 0.214 AC XY: 15883 AN XY: 74274

African (AFR) AF: 0.365 AC: 15131 AN: 41448

American (AMR) AF: 0.311 AC: 4744 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 544 AN: 3466

East Asian (EAS) AF: 0.211 AC: 1088 AN: 5148

South Asian (SAS) AF: 0.214 AC: 1033 AN: 4816

European-Finnish (FIN) AF: 0.123 AC: 1307 AN: 10588

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7931 AN: 67944

Other (OTH) AF: 0.204 AC: 430 AN: 2106

Alfa AF: 0.175 Hom.: 400

Bravo AF: 0.235

Asia WGS AF: 0.269 AC: 932 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.48
DANN	Benign	0.56
PhyloP100		-1.0
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: rs1414503; hg19: chr6-51522488;