chr6-61732698-C-T

Variant names:

• chr6-61732698-C-T
• rs776278021
• NM_152688.4:c.877G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152688.4(KHDRBS2):​c.877G>A​(p.Ala293Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,455,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A293V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KHDRBS2 NM_152688.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16095874).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152688.4. 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
	KHDRBS2	NM_152688.4	MANE Select	c.877G>A	p.Ala293Thr	missense	Exon 7 of 9	NP_689901.2	Q5VWX1
	KHDRBS2	NM_001350622.2		c.928G>A	p.Ala310Thr	missense	Exon 8 of 10	NP_001337551.1
	KHDRBS2	NR_146870.2		n.1154G>A		non_coding_transcript_exon	Exon 7 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KHDRBS2	ENST00000281156.5	TSL:1 MANE Select	c.877G>A	p.Ala293Thr	missense	Exon 7 of 9	ENSP00000281156.3	Q5VWX1
	KHDRBS2	ENST00000968831.1		c.877G>A	p.Ala293Thr	missense	Exon 7 of 10	ENSP00000638890.1
	KHDRBS2	ENST00000931671.1		c.730G>A	p.Ala244Thr	missense	Exon 6 of 8	ENSP00000601730.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251102 AF XY: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455366 Hom.: 0 Cov.: 26 AF XY: 0.00000276 AC XY: 2 AN XY: 724476

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1106294

Other (OTH) AF: 0.00 AC: 0 AN: 60166

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	Benign	0.072
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.088
Sift	Benign	0.26	T
Sift4G	Benign	0.49	T
Polyphen		0.10	B
Vest4		0.52
MutPred		0.21		Gain of glycosylation at A293 (P = 0.0153)
MVP		0.53
MPC		0.060
ClinPred		0.25	T
GERP RS		5.1
Varity_R		0.10
gMVP		0.20
Mutation Taster		=89/11	polymorphism

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: rs776278021; hg19: chr6-62442603; COSMIC: COSV55485498;