6-61894739-G-T

Position:

• chr6-61894739-G-T

Variant summary

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

The NM_152688.4(KHDRBS2):​c.706C>A​(p.Pro236Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KHDRBS2 NM_152688.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

Genes affected

KHDRBS2 (HGNC:18114): (KH RNA binding domain containing, signal transduction associated 2) Predicted to enable mRNA binding activity and poly(A) binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

KHDRBS2 (HGNC:):

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=0.34592938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDRBS2	NM_152688.4	c.706C>A	p.Pro236Thr	missense_variant	6/9	ENST00000281156.5	NP_689901.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDRBS2	ENST00000281156.5	c.706C>A	p.Pro236Thr	missense_variant	6/9	1	NM_152688.4	ENSP00000281156.3
KHDRBS2	ENST00000675091.1	n.706C>A		non_coding_transcript_exon_variant	6/10			ENSP00000502245.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461320 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 21, 2024

The c.706C>A (p.P236T) alteration is located in exon 6 (coding exon 6) of the KHDRBS2 gene. This alteration results from a C to A substitution at nucleotide position 706, causing the proline (P) at amino acid position 236 to be replaced by a threonine (T). 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	0.061
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Benign	0.047
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.039
Sift	Benign	0.14	T
Sift4G	Benign	0.33	T
Polyphen		0.0070	B
Vest4		0.58
MutPred		0.26		Gain of glycosylation at P236 (P = 0.013);
MVP		0.49
MPC		0.059
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.19
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-62604644;