NM_138694.4:c.5896C>T

Variant names:

• chr6-51959882-G-A
• rs1266923
• NM_138694.4:c.5896C>T

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.5896C>T​(p.Leu1966Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0171 in 1,612,946 control chromosomes in the GnomAD database, including 1,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1966L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.050 (435 hom., cov: 32)
  • Exomes 𝑓: 0.014 (765 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.81
• Publications: 5 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=-0.56).
• BP6: Variant 6-51959882-G-A is Benign according to our data. Variant chr6-51959882-G-A is described in ClinVar as Benign. ClinVar VariationId is 96414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 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.5896C>T	p.Leu1966Leu	synonymous	Exon 36 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.5896C>T	p.Leu1966Leu	synonymous	Exon 36 of 61	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.5896C>T	p.Leu1966Leu	synonymous	Exon 36 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.5896C>T	p.Leu1966Leu	synonymous	Exon 36 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7585 AN: 151988 Hom.: 430 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.0367

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.0454

GnomAD2 exomes AF: 0.0320 AC: 8041 AN: 251106 AF XY: 0.0301

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0137 AC: 19941 AN: 1460840 Hom.: 765 Cov.: 31 AF XY: 0.0140 AC XY: 10186 AN XY: 726766

African (AFR) AF: 0.132 AC: 4405 AN: 33392

American (AMR) AF: 0.0204 AC: 911 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 287 AN: 26114

East Asian (EAS) AF: 0.0980 AC: 3890 AN: 39678

South Asian (SAS) AF: 0.0343 AC: 2954 AN: 86234

European-Finnish (FIN) AF: 0.0569 AC: 3037 AN: 53410

Middle Eastern (MID) AF: 0.0315 AC: 181 AN: 5754

European-Non Finnish (NFE) AF: 0.00253 AC: 2809 AN: 1111250

Other (OTH) AF: 0.0243 AC: 1467 AN: 60312

GnomAD4 genome AF: 0.0501 AC: 7618 AN: 152106 Hom.: 435 Cov.: 32 AF XY: 0.0526 AC XY: 3910 AN XY: 74366

African (AFR) AF: 0.130 AC: 5373 AN: 41468

American (AMR) AF: 0.0298 AC: 455 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.104 AC: 537 AN: 5156

South Asian (SAS) AF: 0.0365 AC: 176 AN: 4822

European-Finnish (FIN) AF: 0.0657 AC: 696 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 67994

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0203 Hom.: 226

Bravo AF: 0.0504

Asia WGS AF: 0.0780 AC: 272 AN: 3478

EpiCase AF: 0.00546

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Autosomal recessive polycystic kidney disease (5)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.8
DANN	Benign	0.50
PhyloP100		3.8
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1266923; hg19: chr6-51824680; COSMIC: COSV61877425;