rs1896976

Variant names:

• chr6-52059976-A-G
• rs1896976
• NM_138694.4:c.1185T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-52059976-A-G
• chr6-52059976-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):​c.1185T>C​(p.Asp395Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,609,952 control chromosomes in the GnomAD database, including 794,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71173 hom., cov: 32)
  • Exomes 𝑓: 1.0 (723509 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.409
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 6-52059976-A-G is Benign according to our data. Variant chr6-52059976-A-G is described in ClinVar as Benign. ClinVar VariationId is 96374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.409 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.1185T>C	p.Asp395Asp	synonymous	Exon 15 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.1185T>C	p.Asp395Asp	synonymous	Exon 15 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.1185T>C	p.Asp395Asp	synonymous	Exon 15 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.1185T>C	p.Asp395Asp	synonymous	Exon 15 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.965 AC: 146919 AN: 152180 Hom.: 71130 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.973

GnomAD2 exomes AF: 0.990 AC: 248757 AN: 251196 AF XY: 0.993

Gnomad AFR exome AF: 0.873

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1452054 AN: 1457654 Hom.: 723509 Cov.: 32 AF XY: 0.997 AC XY: 723137 AN XY: 725570

African (AFR) AF: 0.876 AC: 29216 AN: 33368

American (AMR) AF: 0.992 AC: 44371 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26066 AN: 26094

East Asian (EAS) AF: 1.00 AC: 39680 AN: 39680

South Asian (SAS) AF: 1.00 AC: 86137 AN: 86168

European-Finnish (FIN) AF: 1.00 AC: 53403 AN: 53404

Middle Eastern (MID) AF: 0.994 AC: 5721 AN: 5756

European-Non Finnish (NFE) AF: 1.00 AC: 1107749 AN: 1108230

Other (OTH) AF: 0.991 AC: 59711 AN: 60236

GnomAD4 genome AF: 0.965 AC: 147020 AN: 152298 Hom.: 71173 Cov.: 32 AF XY: 0.967 AC XY: 72027 AN XY: 74466

African (AFR) AF: 0.881 AC: 36566 AN: 41526

American (AMR) AF: 0.986 AC: 15094 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3468 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5190 AN: 5190

South Asian (SAS) AF: 1.00 AC: 4823 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67991 AN: 68036

Other (OTH) AF: 0.974 AC: 2058 AN: 2114

Alfa AF: 0.983 Hom.: 38139

Bravo AF: 0.960

Asia WGS AF: 0.993 AC: 3454 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.0
DANN	Benign	0.73
PhyloP100		0.41
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1896976; hg19: chr6-51924774; COSMIC: COSV108168664;