NM_031941.4:c.2038G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E680K) has been classified as Uncertain significance.

• 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
• Publications: 4 publications found

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

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=0.15308931).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031941.4. 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
	USHBP1	NM_031941.4	MANE Select	c.2038G>C	p.Glu680Gln	missense	Exon 13 of 13	NP_114147.2
	USHBP1	NM_001321417.2		c.2038G>C	p.Glu680Gln	missense	Exon 13 of 13	NP_001308346.1	Q8N6Y0-1
	USHBP1	NM_001297703.2		c.1846G>C	p.Glu616Gln	missense	Exon 12 of 12	NP_001284632.1	G8JLM4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USHBP1	ENST00000252597.8	TSL:1 MANE Select	c.2038G>C	p.Glu680Gln	missense	Exon 13 of 13	ENSP00000252597.2	Q8N6Y0-1
	ENSG00000269095	ENST00000594059.1	TSL:4	c.-83+1283G>C		intron	N/A	ENSP00000473056.1	M0R384
	USHBP1	ENST00000881047.1		c.2038G>C	p.Glu680Gln	missense	Exon 12 of 12	ENSP00000551106.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249182 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: 0.00000890

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

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52882

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.042
Sift	Benign	0.14	T
Sift4G	Benign	0.32	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs756523964; hg19: chr19-17361108;