13-50015908-A-G

Position:

• chr13-50015908-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173605.2(KCNRG):​c.415A>G​(p.Arg139Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 30)
• Consequence: KCNRG NM_173605.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

KCNRG (HGNC:18893): (potassium channel regulator) This gene encodes a protein which regulates the activity of voltage-gated potassium channels. This gene is on chromosome 13 and overlaps the gene for tripartite motif containing 13 on the same strand. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

TRIM13 (HGNC:9976): (tripartite motif containing 13) This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This gene is located on chromosome 13 within the minimal deletion region for B-cell chronic lymphocytic leukemia. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

DLEU2 (HGNC:13748): (deleted in lymphocytic leukemia 2) This locus represents a microRNA host gene and also produces long alternatively spliced non-coding RNAs. This genome region was observed to be deleted or epigenetically suppressed in leukemia, and was implicated as a negative regulator of cell proliferation. However, an alternative transcript produced at this locus was also found to promote progression through the cell cycle via angiotensin I converting enzyme 2 and cyclin D1. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27028123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNRG	NM_173605.2	c.415A>G	p.Arg139Gly	missense_variant	1/2	ENST00000312942.2	NP_775876.1
TRIM13	NM_213590.3	c.*2744A>G		3_prime_UTR_variant	2/2	ENST00000378182.4	NP_998755.1
DLEU2	NR_152566.1	n.1314+11299T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNRG	ENST00000312942.2	c.415A>G	p.Arg139Gly	missense_variant	1/2	1	NM_173605.2	ENSP00000324191	P1
TRIM13	ENST00000378182.4	c.*2744A>G		3_prime_UTR_variant	2/2	1	NM_213590.3	ENSP00000367424	P4
DLEU2	ENST00000621282.4	n.1314+11299T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.415A>G (p.R139G) alteration is located in exon 1 (coding exon 1) of the KCNRG gene. This alteration results from a A to G substitution at nucleotide position 415, causing the arginine (R) at amino acid position 139 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.66	N;N;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.4	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.98	D;P
Vest4		0.40
MutPred		0.60		Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);
MVP		0.78
MPC		0.17
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.56
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs1255722688; hg19: chr13-50590044;