18-70197682-T-C

Variant names:

• chr18-70197682-T-C
• rs12956068
• NM_173630.4:c.635A>G

Variant summary

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

The NM_173630.4(RTTN):​c.635A>G​(p.Asp212Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D212A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.21
• Publications: 11 publications found

Genes affected

RTTN (HGNC:18654): (rotatin) This gene encodes a large protein whose specific function is unknown. Absence of the orthologous protein in mouse results in embryonic lethality with deficient axial rotation, abnormal differentiation of the neural tube, and randomized looping of the heart tube during development. In human, mutations in this gene are associated with polymicrogyria with seizures. In human fibroblasts this protein localizes at the ciliary basal bodies. Given the intracellular localization of this protein and the phenotypic effects of mutations, this gene is suspected of playing a role in the maintenance of normal ciliary structure which in turn effects the developmental process of left-right organ specification, axial rotation, and perhaps notochord development. [provided by RefSeq, Jan 2013]

RTTN Gene-Disease associations (from GenCC):

• microcephalic primordial dwarfism due to RTTN deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.635A>G	p.Asp212Gly	missense_variant	Exon 6 of 49	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.635A>G	p.Asp212Gly	missense_variant	Exon 6 of 49	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 4

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.28	T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.7	M;M;.
PhyloP100		6.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	.;D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.019	.;D;.
Sift4G	Uncertain	0.016	.;D;.
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.42		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;
MVP		0.43
MPC		0.47
ClinPred		0.96	D
GERP RS		3.4
Varity_R		0.39
gMVP		0.77
Mutation Taster		=83/17	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: rs12956068; hg19: chr18-67864918;