6-52056816-A-G

Variant names:

• chr6-52056816-A-G
• rs73435705
• NM_138694.4:c.1603-28T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138694.4(PKHD1):​c.1603-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,595,814 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (15 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0150
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-52056816-A-G is Benign according to our data. Variant chr6-52056816-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00772 (1176/152284) while in subpopulation AFR AF = 0.0271 (1127/41550). AF 95% confidence interval is 0.0258. There are 17 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.1603-28T>C		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.1603-28T>C		intron	N/A	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.1603-28T>C		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.1603-28T>C		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1174 AN: 152166 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00192 AC: 481 AN: 250912 AF XY: 0.00142

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000872 AC: 1259 AN: 1443530 Hom.: 15 Cov.: 26 AF XY: 0.000772 AC XY: 555 AN XY: 719378

African (AFR) AF: 0.0291 AC: 963 AN: 33098

American (AMR) AF: 0.00157 AC: 70 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.000186 AC: 16 AN: 85952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00401 AC: 23 AN: 5738

European-Non Finnish (NFE) AF: 0.0000721 AC: 79 AN: 1095276

Other (OTH) AF: 0.00174 AC: 104 AN: 59774

GnomAD4 genome AF: 0.00772 AC: 1176 AN: 152284 Hom.: 17 Cov.: 32 AF XY: 0.00733 AC XY: 546 AN XY: 74474

African (AFR) AF: 0.0271 AC: 1127 AN: 41550

American (AMR) AF: 0.00196 AC: 30 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00894

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive polycystic kidney disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.68
PhyloP100		-0.015
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs73435705; hg19: chr6-51921614;