NM_002256.4:c.*70C>G

Variant names:

• chr1-204190414-G-C
• rs1132506
• NM_002256.4:c.*70C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002256.4(KISS1):​c.*70C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 505,596 control chromosomes in the GnomAD database, including 27,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (10832 hom., cov: 21)
  • Exomes 𝑓: 0.26 (16779 hom.)
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 6 publications found

Genes affected

KISS1 (HGNC:6341): (KiSS-1 metastasis suppressor) This gene is a metastasis suppressor gene that suppresses metastases of melanomas and breast carcinomas without affecting tumorigenicity. The encoded protein may inhibit chemotaxis and invasion and thereby attenuate metastasis in malignant melanomas. Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization. A protein product of this gene, kisspeptin, stimulates gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion and regulates the pubertal activation of GnRH neurons. A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues. [provided by RefSeq, Jun 2022]

REN (HGNC:9958): (renin) This gene encodes renin, an aspartic protease that is secreted by the kidneys. Renin is a part of the renin-angiotensin-aldosterone system involved in regulation of blood pressure, and electrolyte balance. This enzyme catalyzes the first step in the activation pathway of angiotensinogen by cleaving angiotensinogen to form angiotensin I, which is then converted to angiotensin II by angiotensin I converting enzyme. This cascade can result in aldosterone release, narrowing of blood vessels, and increase in blood pressure as angiotension II is a vasoconstrictive peptide. Transcript variants that encode different protein isoforms and that arise from alternative splicing and the use of alternative promoters have been described, but their full-length nature has not been determined. Mutations in this gene have been shown to cause hyperuricemic nephropathy familial juvenile 2, familial hyperproreninemia, and renal tubular dysgenesis. [provided by RefSeq, May 2020]

REN Gene-Disease associations (from GenCC):

• familial juvenile hyperuricemic nephropathy type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-204190414-G-C is Benign according to our data. Variant chr1-204190414-G-C is described in ClinVar as Benign. ClinVar VariationId is 1291541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002256.4. 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
	KISS1	NM_002256.4	MANE Select	c.*70C>G		3_prime_UTR	Exon 3 of 3	NP_002247.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	ENST00000367194.5	TSL:1 MANE Select	c.*70C>G		3_prime_UTR	Exon 3 of 3	ENSP00000356162.4	Q15726
	KISS1	ENST00000882445.1		c.*70C>G		3_prime_UTR	Exon 2 of 2	ENSP00000552504.1
	REN	ENST00000638118.1	TSL:5	c.-393C>G		upstream_gene	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes AF: 0.431 AC: 50297 AN: 116610 Hom.: 10794 Cov.: 21

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.400

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.262 AC: 101992 AN: 388892 Hom.: 16779 Cov.: 4 AF XY: 0.271 AC XY: 55650 AN XY: 205232

African (AFR) AF: 0.609 AC: 4516 AN: 7410

American (AMR) AF: 0.431 AC: 8814 AN: 20468

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 3729 AN: 11566

East Asian (EAS) AF: 0.345 AC: 7089 AN: 20570

South Asian (SAS) AF: 0.348 AC: 15487 AN: 44492

European-Finnish (FIN) AF: 0.210 AC: 4299 AN: 20500

Middle Eastern (MID) AF: 0.344 AC: 479 AN: 1394

European-Non Finnish (NFE) AF: 0.216 AC: 52302 AN: 242636

Other (OTH) AF: 0.266 AC: 5277 AN: 19856

GnomAD4 genome AF: 0.432 AC: 50390 AN: 116704 Hom.: 10832 Cov.: 21 AF XY: 0.428 AC XY: 24124 AN XY: 56340

African (AFR) AF: 0.655 AC: 19241 AN: 29360

American (AMR) AF: 0.416 AC: 5030 AN: 12092

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1029 AN: 2778

East Asian (EAS) AF: 0.452 AC: 2072 AN: 4580

South Asian (SAS) AF: 0.292 AC: 1088 AN: 3720

European-Finnish (FIN) AF: 0.296 AC: 2212 AN: 7474

Middle Eastern (MID) AF: 0.415 AC: 98 AN: 236

European-Non Finnish (NFE) AF: 0.346 AC: 18749 AN: 54164

Other (OTH) AF: 0.410 AC: 660 AN: 1608

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.18
PhyloP100		0.0
PromoterAI		-0.067	Neutral
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: rs1132506; hg19: chr1-204159542;