chr6-51632744-T-C

Variant names:

• chr6-51632744-T-C
• rs2174860
• NM_138694.4:c.11507-21A>G

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.11507-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,598,530 control chromosomes in the GnomAD database, including 965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (234 hom., cov: 32)
  • Exomes 𝑓: 0.028 (731 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.80
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-51632744-T-C is Benign according to our data. Variant chr6-51632744-T-C is described in ClinVar as Benign. ClinVar VariationId is 262385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0902 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.11507-21A>G		intron	N/A	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.11507-21A>G		intron	N/A	ENSP00000360158.3

Frequencies

GnomAD3 genomes AF: 0.0427 AC: 6492 AN: 151942 Hom.: 233 Cov.: 32

Gnomad AFR AF: 0.0927

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0383

GnomAD2 exomes AF: 0.0273 AC: 6821 AN: 250118 AF XY: 0.0262

Gnomad AFR exome AF: 0.0940

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.000328

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0267

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0275 AC: 39795 AN: 1446470 Hom.: 731 Cov.: 28 AF XY: 0.0270 AC XY: 19435 AN XY: 720832

African (AFR) AF: 0.0955 AC: 3149 AN: 32960

American (AMR) AF: 0.0291 AC: 1298 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 712 AN: 25972

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39542

South Asian (SAS) AF: 0.0202 AC: 1739 AN: 85936

European-Finnish (FIN) AF: 0.0138 AC: 736 AN: 53302

Middle Eastern (MID) AF: 0.0159 AC: 91 AN: 5718

European-Non Finnish (NFE) AF: 0.0277 AC: 30484 AN: 1098580

Other (OTH) AF: 0.0264 AC: 1583 AN: 59878

GnomAD4 genome AF: 0.0428 AC: 6502 AN: 152060 Hom.: 234 Cov.: 32 AF XY: 0.0413 AC XY: 3069 AN XY: 74356

African (AFR) AF: 0.0926 AC: 3842 AN: 41472

American (AMR) AF: 0.0254 AC: 388 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4812

European-Finnish (FIN) AF: 0.0106 AC: 112 AN: 10562

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0269 AC: 1826 AN: 67988

Other (OTH) AF: 0.0379 AC: 80 AN: 2110

Alfa AF: 0.0346 Hom.: 41

Bravo AF: 0.0470

Asia WGS AF: 0.0180 AC: 63 AN: 3476

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0090
DANN	Benign	0.28
PhyloP100		-2.8
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: rs2174860; hg19: chr6-51497542;