6-51616527-A-AT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_138694.4(PKHD1):c.*2553_*2554insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 357,738 control chromosomes in the GnomAD database, including 658 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.10 (653 hom., cov: 28)
  • Exomes 𝑓: 0.12 (5 hom.)
• Consequence: PKHD1 NM_138694.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0790

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.*2553_*2554insA		3_prime_UTR_variant	67/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.*2553_*2554insA		3_prime_UTR_variant	67/67	1	NM_138694.4	P2
	ENST00000589278.6	n.811-5818dup		intron_variant, non_coding_transcript_variant		5
	ENST00000454361.1	n.81-5813dup		intron_variant, non_coding_transcript_variant		3
	ENST00000650088.1	n.222-5813dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.100 AC: 14152 AN: 141108 Hom.: 654 Cov.: 28

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0977

Gnomad AMR AF: 0.0804

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0912

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.0331

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0871

GnomAD4 exome AF: 0.118 AC: 25656 AN: 216580 Hom.: 5 Cov.: 0 AF XY: 0.118 AC XY: 12983 AN XY: 110112

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.0932

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.100 AC: 14167 AN: 141158 Hom.: 653 Cov.: 28 AF XY: 0.0984 AC XY: 6724 AN XY: 68340

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0803

Gnomad4 ASJ AF: 0.0933

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.0914

Gnomad4 FIN AF: 0.0967

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0874

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs113144792; hg19: chr6-51481325;