chr7-6757867-G-A

Variant names:

• chr7-6757867-G-A
• rs754477592
• NM_001099697.2:c.190G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001099697.2(RSPH10B2):​c.190G>A​(p.Val64Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 144,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000062 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: RSPH10B2 NM_001099697.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.80

Genes affected

RSPH10B2 (HGNC:34385): (radial spoke head 10 homolog B2) This gene encodes a protein component of the radial spoke head in flagella and motile cilia. Eukaryotic flagella and motile cilia share a common 9 + 2 structure, in which nine peripheral microtubule doublets (MTDs) surround a central-pair of microtubules (CP), with radial spokes connecting the MTDs to the CP. The radial spoke is a multi-protein complex that works as a mechanochemical transducer between the CP and the MTDs. The radial spoke contributes to the regulation of the activity of dynein motors, and thus to flagellar motility. PMID: 22754630 provides a good review of radial spokes. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053362846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH10B2	NM_001099697.2	c.190G>A	p.Val64Ile	missense_variant	Exon 3 of 21	ENST00000404077.6	NP_001093167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH10B2	ENST00000404077.6	c.190G>A	p.Val64Ile	missense_variant	Exon 3 of 21	1	NM_001099697.2	ENSP00000386102.1

Frequencies

GnomAD3 genomes AF: 0.0000207 AC: 3 AN: 144848 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000691

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000670 AC: 16 AN: 238870 AF XY: 0.0000310

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000825

Gnomad OTH exome AF: 0.000168

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000617 AC: 88 AN: 1425532 Hom.: 2 Cov.: 31 AF XY: 0.0000536 AC XY: 38 AN XY: 708310

Gnomad4 AFR exome AF: 0.000252 AC: 8 AN: 31756

Gnomad4 AMR exome AF: 0.000162 AC: 7 AN: 43202

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25478

Gnomad4 EAS exome AF: 0.0000279 AC: 1 AN: 35862

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 79976

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52990

Gnomad4 NFE exome AF: 0.0000632 AC: 69 AN: 1092254

Gnomad4 Remaining exome AF: 0.0000342 AC: 2 AN: 58508

GnomAD4 genome AF: 0.0000207 AC: 3 AN: 144848 Hom.: 0 Cov.: 23 AF XY: 0.0000284 AC XY: 2 AN XY: 70514

Gnomad4 AFR AF: 0.0000519 AC: 0.0000519238 AN: 0.0000519238

Gnomad4 AMR AF: 0.0000691 AC: 0.0000691085 AN: 0.0000691085

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000665 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.190G>A (p.V64I) alteration is located in exon 3 (coding exon 1) of the RSPH10B2 gene. This alteration results from a G to A substitution at nucleotide position 190, causing the valine (V) at amino acid position 64 to be replaced by an isoleucine (I). 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	0.065
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0070
DANN	Benign	0.94
DEOGEN2	Benign	0.00082	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.17	.;.;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.056
MutPred		0.23		Loss of ubiquitination at K59 (P = 0.1087);Loss of ubiquitination at K59 (P = 0.1087);Loss of ubiquitination at K59 (P = 0.1087);
MVP		0.030
ClinPred		0.015	T
GERP RS		1.4
Varity_R		0.044
gMVP		0.059
Mutation Taster		=300/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs754477592; hg19: chr7-6797498; COSMIC: COSV51867563; COSMIC: COSV51867563;