6-52066088-TAAAA-TAAA

Variant names:

• chr6-52066088-TA-T
• rs5876252
• NM_138694.4:c.779-12delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.779-12delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0098 (29 hom., cov: 0)
  • Exomes 𝑓: 0.047 (0 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.169
• 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: Orphanet, ClinGen, Myriad Women's Health
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 6-52066088-TA-T is Benign according to our data. Variant chr6-52066088-TA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357455.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00981 (1412/143978) while in subpopulation AFR AF = 0.0302 (1183/39162). AF 95% confidence interval is 0.0288. There are 29 homozygotes in GnomAd4. There are 649 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.779-12delT		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.779-12delT		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.779-12delT		intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.779-12delT		intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1408 AN: 143946 Hom.: 29 Cov.: 0

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00637

Gnomad ASJ AF: 0.000588

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.000882

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0127

GnomAD2 exomes AF: 0.0587 AC: 10383 AN: 176846 AF XY: 0.0593

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.0521

Gnomad EAS exome AF: 0.0384

Gnomad FIN exome AF: 0.0450

Gnomad NFE exome AF: 0.0553

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0475 AC: 37208 AN: 783414 Hom.: 0 Cov.: 13 AF XY: 0.0468 AC XY: 19237 AN XY: 411224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.118 AC: 2352 AN: 19958

American (AMR) AF: 0.0410 AC: 1521 AN: 37110

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 858 AN: 20086

East Asian (EAS) AF: 0.0283 AC: 914 AN: 32332

South Asian (SAS) AF: 0.0597 AC: 3845 AN: 64364

European-Finnish (FIN) AF: 0.0357 AC: 1443 AN: 40420

Middle Eastern (MID) AF: 0.0350 AC: 140 AN: 4002

European-Non Finnish (NFE) AF: 0.0461 AC: 24357 AN: 528530

Other (OTH) AF: 0.0486 AC: 1778 AN: 36612

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00981 AC: 1412 AN: 143978 Hom.: 29 Cov.: 0 AF XY: 0.00931 AC XY: 649 AN XY: 69682

African (AFR) AF: 0.0302 AC: 1183 AN: 39162

American (AMR) AF: 0.00636 AC: 92 AN: 14472

Ashkenazi Jewish (ASJ) AF: 0.000588 AC: 2 AN: 3402

East Asian (EAS) AF: 0.000200 AC: 1 AN: 5002

South Asian (SAS) AF: 0.000887 AC: 4 AN: 4508

European-Finnish (FIN) AF: 0.00368 AC: 30 AN: 8156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.00113 AC: 75 AN: 66122

Other (OTH) AF: 0.0126 AC: 25 AN: 1982

Alfa AF: 0.0694 Hom.: 42

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5876252; hg19: chr6-51930886;