6-61681007-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152688.4(KHDRBS2):c.1006T>C(p.Ser336Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,459,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KHDRBS2 NM_152688.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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-OT1 (HGNC:53911): (KHDRBS2 3'UTR overlapping transcript 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05745122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KHDRBS2	NM_152688.4	c.1006T>C	p.Ser336Pro	missense_variant	9/9	ENST00000281156.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KHDRBS2	ENST00000281156.5	c.1006T>C	p.Ser336Pro	missense_variant	9/9	1	NM_152688.4	P1
KHDRBS2-OT1	ENST00000511849.2	n.43T>C		non_coding_transcript_exon_variant	1/6	3
KHDRBS2	ENST00000675091.1	c.*162T>C		3_prime_UTR_variant, NMD_transcript_variant	10/10

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1459834 Hom.: 0 Cov.: 28 AF XY: 0.00000688 AC XY: 5 AN XY: 726310

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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 05, 2023

The c.1006T>C (p.S336P) alteration is located in exon 9 (coding exon 9) of the KHDRBS2 gene. This alteration results from a T to C substitution at nucleotide position 1006, causing the serine (S) at amino acid position 336 to be replaced by a proline (P). 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	0.075
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	14
Dann	Benign	0.75
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.23	N
MutationTaster	Benign	0.93	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.029
Sift	Benign	0.66	T
Sift4G	Benign	0.37	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.20		Loss of phosphorylation at S336 (P = 0.0081);
MVP		0.30
MPC		0.065
ClinPred		0.061	T
GERP RS		2.6
Varity_R		0.10
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1766233127; hg19: chr6-62390912;