6-51911962-GAAA-GA

Variant names:

• chr6-51911962-GAA-G
• rs138161138
• NM_138694.4:c.6333-8_6333-7delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.6333-8_6333-7delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,606,474 control chromosomes in the GnomAD database, including 630 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (331 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (299 hom.)
• Consequence: PKHD1 NM_138694.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.41
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 6-51911962-GAA-G is Benign according to our data. Variant chr6-51911962-GAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 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.6333-8_6333-7delTT		splice_region intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.6333-8_6333-7delTT		splice_region 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.6333-8_6333-7delTT		splice_region intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.6333-8_6333-7delTT		splice_region intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5284 AN: 151710 Hom.: 329 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.00901 AC: 2221 AN: 246380 AF XY: 0.00671

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00357 AC: 5199 AN: 1454644 Hom.: 299 AF XY: 0.00310 AC XY: 2242 AN XY: 724032

African (AFR) AF: 0.128 AC: 4268 AN: 33218

American (AMR) AF: 0.00614 AC: 273 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86070

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 51986

Middle Eastern (MID) AF: 0.00888 AC: 51 AN: 5746

European-Non Finnish (NFE) AF: 0.0000984 AC: 109 AN: 1107378

Other (OTH) AF: 0.00793 AC: 477 AN: 60114

GnomAD4 genome AF: 0.0349 AC: 5298 AN: 151830 Hom.: 331 Cov.: 32 AF XY: 0.0343 AC XY: 2544 AN XY: 74188

African (AFR) AF: 0.122 AC: 5035 AN: 41414

American (AMR) AF: 0.0122 AC: 186 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67916

Other (OTH) AF: 0.0242 AC: 51 AN: 2108

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.0404

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs138161138; hg19: chr6-51776760;