6-51748214-C-T

Variant names:

• chr6-51748214-C-T
• rs143737660
• NM_138694.4:c.9402G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_138694.4(PKHD1):​c.9402G>A​(p.Lys3134Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,614,046 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 0.613
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-51748214-C-T is Benign according to our data. Variant chr6-51748214-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357418.
• BP7: Synonymous conserved (PhyloP=0.613 with no splicing effect.

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.9402G>A	p.Lys3134Lys	synonymous	Exon 58 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.9402G>A	p.Lys3134Lys	synonymous	Exon 58 of 61	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.9402G>A	p.Lys3134Lys	synonymous	Exon 58 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.9402G>A	p.Lys3134Lys	synonymous	Exon 58 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000415 AC: 104 AN: 250836 AF XY: 0.000428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000289 AC: 423 AN: 1461792 Hom.: 1 Cov.: 34 AF XY: 0.000315 AC XY: 229 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000403 AC: 18 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000234 AC: 260 AN: 1111952

Other (OTH) AF: 0.000729 AC: 44 AN: 60392

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74440

African (AFR) AF: 0.0000481 AC: 2 AN: 41554

American (AMR) AF: 0.000851 AC: 13 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000414 Hom.: 0

Bravo AF: 0.000355

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.5
DANN	Benign	0.53
PhyloP100		0.61
Mutation Taster		=94/6	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: rs143737660; hg19: chr6-51613012;