13-45193896-C-G

Variant names:

• chr13-45193896-C-G
• rs1566130326
• NM_198404.3:c.672G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198404.3(KCTD4):​c.672G>C​(p.Lys224Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCTD4 NM_198404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

Genes affected

KCTD4 (HGNC:23227): (potassium channel tetramerization domain containing 4) Predicted to be involved in protein homooligomerization. [provided by Alliance of Genome Resources, Apr 2022]

GTF2F2 (HGNC:4653): (general transcription factor IIF subunit 2) Predicted to enable RNA polymerase II general transcription initiation factor activity. Involved in transcription by RNA polymerase II. Located in microtubule cytoskeleton and nucleoplasm. Part of transcription preinitiation complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198404.3. 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
	KCTD4	NM_198404.3	MANE Select	c.672G>C	p.Lys224Asn	missense	Exon 2 of 2	NP_940686.2	Q8WVF5
	GTF2F2	NM_004128.3	MANE Select	c.305-13528C>G		intron	N/A	NP_004119.1	P13984

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD4	ENST00000379108.2	TSL:6 MANE Select	c.672G>C	p.Lys224Asn	missense	Exon 2 of 2	ENSP00000368402.1	Q8WVF5
	GTF2F2	ENST00000340473.8	TSL:1 MANE Select	c.305-13528C>G		intron	N/A	ENSP00000340823.6	P13984
	GTF2F2	ENST00000883031.1		c.382+10418C>G		intron	N/A	ENSP00000553090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250740 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.21
Sift	Benign	0.079	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.49		Gain of catalytic residue at F225 (P = 0)
MVP		0.77
ClinPred		0.90	D
GERP RS		6.0
Varity_R		0.29
gMVP		0.88
Mutation Taster		=41/59	disease causing

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: rs1566130326; hg19: chr13-45768031;