chr2-9630249-C-G

Variant names:

• chr2-9630249-C-G
• NM_006826.4:c.204G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006826.4(YWHAQ):​c.204G>C​(p.Lys68Asn) 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 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K68T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: YWHAQ NM_006826.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.119

Genes affected

YWHAQ (HGNC:12854): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta) This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse and rat orthologs. This gene is upregulated in patients with amyotrophic lateral sclerosis. It contains in its 5' UTR a 6 bp tandem repeat sequence which is polymorphic, however, there is no correlation between the repeat number and the disease. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue N6-acetyllysine (size 0) in uniprot entity 1433T_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YWHAQ	NM_006826.4	c.204G>C	p.Lys68Asn	missense_variant	Exon 2 of 6	ENST00000238081.8	NP_006817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YWHAQ	ENST00000238081.8	c.204G>C	p.Lys68Asn	missense_variant	Exon 2 of 6	1	NM_006826.4	ENSP00000238081.3
YWHAQ	ENST00000381844.8	c.204G>C	p.Lys68Asn	missense_variant	Exon 1 of 5	1		ENSP00000371267.4
YWHAQ	ENST00000446619.1	c.204G>C	p.Lys68Asn	missense_variant	Exon 2 of 4	3		ENSP00000398990.1
YWHAQ	ENST00000460093.1	n.20G>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727200

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: 0.00000180

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

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.204G>C (p.K68N) alteration is located in exon 2 (coding exon 1) of the YWHAQ gene. This alteration results from a G to C substitution at nucleotide position 204, causing the lysine (K) at amino acid position 68 to be replaced by an asparagine (N). 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	0.97
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.83	.;T;T
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.1	M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.014	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.79
MutPred		0.67		Loss of ubiquitination at K68 (P = 0.0063);Loss of ubiquitination at K68 (P = 0.0063);Loss of ubiquitination at K68 (P = 0.0063);
MVP		0.68
MPC		1.8
ClinPred		1.0	D
GERP RS		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.67

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: chr2-9770378;