19-1854596-G-A

Variant names:

• chr19-1854596-G-A
• rs1253660958
• NM_031918.4:c.622C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031918.4(KLF16):​c.622C>T​(p.Arg208Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLF16 NM_031918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

Genes affected

KLF16 (HGNC:16857): (KLF transcription factor 16) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within dopamine receptor signaling pathway. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF16	NM_031918.4	c.622C>T	p.Arg208Cys	missense_variant	Exon 2 of 2	ENST00000250916.6	NP_114124.1
KLF16	XM_047439498.1	c.592C>T	p.Arg198Cys	missense_variant	Exon 2 of 2		XP_047295454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF16	ENST00000250916.6	c.622C>T	p.Arg208Cys	missense_variant	Exon 2 of 2	1	NM_031918.4	ENSP00000250916.3
KLF16	ENST00000617223.1	c.622C>T	p.Arg208Cys	missense_variant	Exon 2 of 3	1		ENSP00000483701.1
KLF16	ENST00000541015.5	n.622C>T		non_coding_transcript_exon_variant	Exon 2 of 3	1		ENSP00000439973.1
KLF16	ENST00000592313.1	c.211C>T	p.Arg71Cys	missense_variant	Exon 2 of 2	3		ENSP00000480570.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440698 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 716848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.622C>T (p.R208C) alteration is located in exon 2 (coding exon 2) of the KLF16 gene. This alteration results from a C to T substitution at nucleotide position 622, causing the arginine (R) at amino acid position 208 to be replaced by a cysteine (C). 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	Pathogenic	0.88
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.069	T;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.45	N
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.2	D;.;.
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.36
MutPred		0.47		Loss of MoRF binding (P = 0.0078);Loss of MoRF binding (P = 0.0078);.;
MVP		0.58
MPC		1.7
ClinPred		0.97	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.57
gMVP		0.75

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: rs1253660958; hg19: chr19-1854595;