6-51616527-A-ATT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_138694.4(PKHD1):c.*2553_*2554insAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 359,846 control chromosomes in the GnomAD database, including 32 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.019 (32 hom., cov: 28)
  • Exomes 𝑓: 0.012 (0 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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0187 (2642/141274) while in subpopulation AFR AF= 0.0258 (993/38504). AF 95% confidence interval is 0.0245. There are 32 homozygotes in gnomad4. There are 1225 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.*2553_*2554insAA		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_*2554insAA		3_prime_UTR_variant	67/67	1	NM_138694.4	P2
	ENST00000589278.6	n.811-5819_811-5818dup		intron_variant, non_coding_transcript_variant		5
	ENST00000454361.1	n.81-5814_81-5813dup		intron_variant, non_coding_transcript_variant		3
	ENST00000650088.1	n.222-5814_222-5813dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2642 AN: 141226 Hom.: 31 Cov.: 28

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.0148

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00727

Gnomad EAS AF: 0.00184

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.00916

Gnomad MID AF: 0.00993

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0141

GnomAD4 exome AF: 0.0121 AC: 2635 AN: 218572 Hom.: 0 Cov.: 0 AF XY: 0.0119 AC XY: 1328 AN XY: 111144

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.00744

Gnomad4 EAS exome AF: 0.00574

Gnomad4 SAS exome AF: 0.00927

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0187 AC: 2642 AN: 141274 Hom.: 32 Cov.: 28 AF XY: 0.0179 AC XY: 1225 AN XY: 68410

Gnomad4 AFR AF: 0.0258

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.00727

Gnomad4 EAS AF: 0.00185

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.00916

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.0140

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

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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: rs113144792; hg19: chr6-51481325;