chr19-45802149-G-A

Variant names:

• chr19-45802149-G-A
• rs201992328
• NM_030785.4:c.1769C>T

Variant summary

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

The NM_030785.4(RSPH6A):​c.1769C>T​(p.Pro590Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000516 in 1,551,734 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. P590R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RSPH6A NM_030785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34
• Publications: 3 publications found

Genes affected

RSPH6A (HGNC:14241): (radial spoke head 6 homolog A) The protein encoded by this gene is similar to a sea urchin radial spoke head protein. Radial spoke protein complexes form part of the axoneme of eukaryotic flagella and are located between the axoneme's outer ring of doublet microtubules and central pair of microtubules. In Chlamydomonas, radial spoke proteins are thought to regulate the activity of dynein and the symmetry of flagellar bending patterns. This gene maps to a region of chromosome 19 that is linked to primary ciliary dyskinesia-2 (CILD2). [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030785.4. 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
	RSPH6A	NM_030785.4	MANE Select	c.1769C>T	p.Pro590Leu	missense	Exon 4 of 6	NP_110412.1	Q9H0K4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH6A	ENST00000221538.8	TSL:1 MANE Select	c.1769C>T	p.Pro590Leu	missense	Exon 4 of 6	ENSP00000221538.2	Q9H0K4
	RSPH6A	ENST00000597055.1	TSL:1	c.1769C>T	p.Pro590Leu	missense	Exon 4 of 6	ENSP00000472630.1	M0R2K1
	RSPH6A	ENST00000600188.5	TSL:2	c.977C>T	p.Pro326Leu	missense	Exon 3 of 5	ENSP00000471559.1	M0R103

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000462 AC: 1 AN: 216318 AF XY: 0.00000848

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: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399406 Hom.: 0 Cov.: 32 AF XY: 0.00000287 AC XY: 2 AN XY: 696052

African (AFR) AF: 0.0000323 AC: 1 AN: 30932

American (AMR) AF: 0.00 AC: 0 AN: 41242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24404

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35296

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075336

Other (OTH) AF: 0.00 AC: 0 AN: 56976

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

African (AFR) AF: 0.0000962 AC: 4 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.28
MPC		0.26
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.56
gMVP		0.52
Mutation Taster		=62/38	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: rs201992328; hg19: chr19-46305407;