6-51856089-GA-GAAA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 1050840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.7734-21_7734-20dupTT		intron_variant	Intron 48 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.7734-20_7734-19insTT		intron_variant	Intron 48 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.7734-20_7734-19insTT		intron_variant	Intron 48 of 60	5		ENSP00000341097.4

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

GnomAD3 exomes AF: 0.00104 AC: 257 AN: 246858 Hom.: 0 AF XY: 0.00113 AC XY: 151 AN XY: 133768

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 SAS exome AF: 0.000531

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

Gnomad4 AFR exome AF: 0.000203

Gnomad4 AMR exome AF: 0.000712

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00110

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

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.00190

Bravo AF: 0.000914

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 21, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.7734-21_7734-20dupTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.001 in 246858 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.001 vs 0.0071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7734-21_7734-20dupTT in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. One locus specific database reports a likely benign outcome. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive polycystic kidney disease Benign:1

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 4 Benign:1

Aug 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201176305; hg19: chr6-51720887;