rs2397060

Variant names:

• chr6-51746672-T-C
• rs2397060
• NM_138694.4:c.9998+49A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-51746672-T-C
• chr6-51746672-T-A

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.9998+49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,162,188 control chromosomes in the GnomAD database, including 31,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (12094 hom., cov: 32)
  • Exomes 𝑓: 0.17 (19359 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.329
• Publications: 15 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=-0.78).
• BP6: Variant 6-51746672-T-C is Benign according to our data. Variant chr6-51746672-T-C is described in ClinVar as Benign. ClinVar VariationId is 262425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 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.9998+49A>G		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.9998+49A>G		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.9998+49A>G		intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.9998+49A>G		intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47456 AN: 152008 Hom.: 12049 Cov.: 32

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.198 AC: 48680 AN: 245730 AF XY: 0.190

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.170 AC: 171685 AN: 1010062 Hom.: 19359 Cov.: 14 AF XY: 0.170 AC XY: 88982 AN XY: 522882

African (AFR) AF: 0.727 AC: 17944 AN: 24692

American (AMR) AF: 0.151 AC: 6603 AN: 43710

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 4471 AN: 23238

East Asian (EAS) AF: 0.185 AC: 6938 AN: 37516

South Asian (SAS) AF: 0.226 AC: 17315 AN: 76630

European-Finnish (FIN) AF: 0.170 AC: 8892 AN: 52290

Middle Eastern (MID) AF: 0.263 AC: 1250 AN: 4744

European-Non Finnish (NFE) AF: 0.141 AC: 99068 AN: 701916

Other (OTH) AF: 0.203 AC: 9204 AN: 45326

GnomAD4 genome AF: 0.313 AC: 47561 AN: 152126 Hom.: 12094 Cov.: 32 AF XY: 0.309 AC XY: 22999 AN XY: 74336

African (AFR) AF: 0.709 AC: 29417 AN: 41466

American (AMR) AF: 0.192 AC: 2931 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 683 AN: 3472

East Asian (EAS) AF: 0.172 AC: 894 AN: 5184

South Asian (SAS) AF: 0.238 AC: 1148 AN: 4828

European-Finnish (FIN) AF: 0.167 AC: 1763 AN: 10588

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10037 AN: 67990

Other (OTH) AF: 0.265 AC: 560 AN: 2114

Alfa AF: 0.194 Hom.: 15792

Bravo AF: 0.330

Asia WGS AF: 0.286 AC: 993 AN: 3476

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	-0.78
CADD	Benign	7.9
DANN	Benign	0.86
PhyloP100		0.33
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: rs2397060; hg19: chr6-51611470;