rs10948667

Variant names:

• chr6-52048442-G-A
• rs10948667
• NM_138694.4:c.2407+50C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-52048442-G-A
• chr6-52048442-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.2407+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,569,940 control chromosomes in the GnomAD database, including 196,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14955 hom., cov: 32)
  • Exomes 𝑓: 0.50 (181522 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.362
• Publications: 10 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), 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=-0.89).
• BP6: Variant 6-52048442-G-A is Benign according to our data. Variant chr6-52048442-G-A is described in ClinVar as Benign. ClinVar VariationId is 262396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

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.2407+50C>T		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.2407+50C>T		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.2407+50C>T		intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.2407+50C>T		intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62597 AN: 151926 Hom.: 14956 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.448

GnomAD2 exomes AF: 0.476 AC: 119662 AN: 251340 AF XY: 0.470

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.497

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.498 AC: 706216 AN: 1417894 Hom.: 181522 Cov.: 24 AF XY: 0.495 AC XY: 350334 AN XY: 708174

African (AFR) AF: 0.145 AC: 4759 AN: 32848

American (AMR) AF: 0.636 AC: 28423 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 12886 AN: 25858

East Asian (EAS) AF: 0.369 AC: 14582 AN: 39498

South Asian (SAS) AF: 0.340 AC: 29061 AN: 85416

European-Finnish (FIN) AF: 0.500 AC: 26666 AN: 53368

Middle Eastern (MID) AF: 0.424 AC: 2410 AN: 5688

European-Non Finnish (NFE) AF: 0.522 AC: 559124 AN: 1071582

Other (OTH) AF: 0.480 AC: 28305 AN: 58956

GnomAD4 genome AF: 0.412 AC: 62599 AN: 152046 Hom.: 14955 Cov.: 32 AF XY: 0.409 AC XY: 30396 AN XY: 74316

African (AFR) AF: 0.159 AC: 6607 AN: 41488

American (AMR) AF: 0.568 AC: 8687 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1749 AN: 3472

East Asian (EAS) AF: 0.382 AC: 1972 AN: 5158

South Asian (SAS) AF: 0.332 AC: 1599 AN: 4818

European-Finnish (FIN) AF: 0.472 AC: 4989 AN: 10560

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35513 AN: 67936

Other (OTH) AF: 0.444 AC: 939 AN: 2114

Alfa AF: 0.489 Hom.: 25678

Bravo AF: 0.410

Asia WGS AF: 0.322 AC: 1123 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive polycystic kidney disease (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.94
DANN	Benign	0.25
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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: rs10948667; hg19: chr6-51913240; COSMIC: COSV61889535;