chr19-17250299-C-G

Variant names:

• chr19-17250299-C-G
• rs756523964
• NM_031941.4:c.2038G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031941.4(USHBP1):​c.2038G>C​(p.Glu680Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USHBP1 NM_031941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

Genes affected

USHBP1 (HGNC:24058): (USH1 protein network component harmonin binding protein 1) Enables PDZ domain binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269095 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15308931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USHBP1	NM_031941.4	c.2038G>C	p.Glu680Gln	missense_variant	Exon 13 of 13	ENST00000252597.8	NP_114147.2
USHBP1	NM_001321417.2	c.2038G>C	p.Glu680Gln	missense_variant	Exon 13 of 13		NP_001308346.1
USHBP1	NM_001297703.2	c.1846G>C	p.Glu616Gln	missense_variant	Exon 12 of 12		NP_001284632.1
USHBP1	NR_135632.2	n.2279G>C		non_coding_transcript_exon_variant	Exon 14 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USHBP1	ENST00000252597.8	c.2038G>C	p.Glu680Gln	missense_variant	Exon 13 of 13	1	NM_031941.4	ENSP00000252597.2
ENSG00000269095	ENST00000594059.1	c.-83+1283G>C		intron_variant	Intron 3 of 4	4		ENSP00000473056.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249182 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135178

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461092 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726876

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.042
Sift	Benign	0.14	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.97	D;.
Vest4		0.24
MutPred		0.17		Gain of MoRF binding (P = 0.0582);.;
MVP		0.41
MPC		0.56
ClinPred		0.62	D
GERP RS		3.5
Varity_R		0.11
gMVP		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs756523964; hg19: chr19-17361108;