chr6-51856089-G-GAA

Variant names:

• chr6-51856089-G-GAA
• rs201176305
• NM_138694.4:c.7734-21_7734-20dupTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_138694.4(PKHD1):​c.7734-21_7734-20dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,448,334 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.207
• Publications: 0 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

ACMG classification

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

• BP6: Variant 6-51856089-G-GAA is Benign according to our data. Variant chr6-51856089-G-GAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1050840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.7734-21_7734-20dupTT		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.7734-21_7734-20dupTT		intron	N/A	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.7734-20_7734-19insTT		intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.7734-20_7734-19insTT		intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.000830 AC: 126 AN: 151772 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00104 AC: 257 AN: 246858 AF XY: 0.00113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000680

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00121 AC: 1568 AN: 1296444 Hom.: 2 Cov.: 22 AF XY: 0.00124 AC XY: 808 AN XY: 654098

African (AFR) AF: 0.000203 AC: 6 AN: 29524

American (AMR) AF: 0.000712 AC: 31 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.00108 AC: 27 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 38122

South Asian (SAS) AF: 0.000441 AC: 36 AN: 81590

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 53142

Middle Eastern (MID) AF: 0.00312 AC: 17 AN: 5454

European-Non Finnish (NFE) AF: 0.00143 AC: 1384 AN: 965550

Other (OTH) AF: 0.00110 AC: 60 AN: 54442

GnomAD4 genome AF: 0.000823 AC: 125 AN: 151890 Hom.: 0 Cov.: 33 AF XY: 0.000768 AC XY: 57 AN XY: 74226

African (AFR) AF: 0.000193 AC: 8 AN: 41454

American (AMR) AF: 0.000720 AC: 11 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 67904

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.000584 Hom.: 0

Bravo AF: 0.000914

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive polycystic kidney disease (1)
-	-	1	not specified (1)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201176305; hg19: chr6-51720887;