rs139306706

Variant names:

• chr6-51748401-G-A
• rs139306706
• NM_138694.4:c.9215C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-51748401-G-A
• chr6-51748401-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.9215C>T​(p.Ala3072Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,972 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3072A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.508
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012168914).
• BP6: Variant 6-51748401-G-A is Benign according to our data. Variant chr6-51748401-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96440.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00125 (1820/1461732) while in subpopulation SAS AF = 0.00863 (744/86256). AF 95% confidence interval is 0.00811. There are 8 homozygotes in GnomAdExome4. There are 1086 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.9215C>T	p.Ala3072Val	missense	Exon 58 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.9215C>T	p.Ala3072Val	missense	Exon 58 of 61	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.9215C>T	p.Ala3072Val	missense	Exon 58 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.9215C>T	p.Ala3072Val	missense	Exon 58 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 152122 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00211 AC: 530 AN: 251036 AF XY: 0.00248

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000934

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00125 AC: 1820 AN: 1461732 Hom.: 8 Cov.: 34 AF XY: 0.00149 AC XY: 1086 AN XY: 727164

African (AFR) AF: 0.0000896 AC: 3 AN: 33466

American (AMR) AF: 0.000761 AC: 34 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 365 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00863 AC: 744 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53408

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000479 AC: 533 AN: 1111920

Other (OTH) AF: 0.00182 AC: 110 AN: 60394

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152240 Hom.: 2 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74428

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.000589 AC: 9 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4822

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: 0.000720 AC: 49 AN: 68014

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00129 Hom.: 2

Bravo AF: 0.000903

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00207 AC: 251

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Autosomal recessive polycystic kidney disease (3)
-	-	2	not specified (2)
-	-	1	PKHD1-related disorder (1)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.6
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.51
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.27
Sift	Benign	0.048	D
Sift4G	Benign	0.069	T
Polyphen		0.63	P
Vest4		0.086
MVP		0.80
MPC		0.063
ClinPred		0.0099	T
GERP RS		0.28
Varity_R		0.040
gMVP		0.82
Mutation Taster		=99/1	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: rs139306706; hg19: chr6-51613199;