chr20-19974990-G-C

Variant names:

• chr20-19974990-G-C
• rs199693970
• NM_018993.4:c.965G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018993.4(RIN2):​c.965G>C​(p.Ser322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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. S322N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RIN2 NM_018993.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65
• Publications: 0 publications found

Genes affected

RIN2 (HGNC:18750): (Ras and Rab interactor 2) The RAB5 protein is a small GTPase involved in membrane trafficking in the early endocytic pathway. The protein encoded by this gene binds the GTP-bound form of the RAB5 protein preferentially over the GDP-bound form, and functions as a guanine nucleotide exchange factor for RAB5. The encoded protein is found primarily as a tetramer in the cytoplasm and does not bind other members of the RAB family. Mutations in this gene cause macrocephaly alopecia cutis laxa and scoliosis (MACS) syndrome, an elastic tissue disorder, as well as the related connective tissue disorder, RIN2 syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2011]

RIN2 Gene-Disease associations (from GenCC):

• RIN2 syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

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=0.22303513).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018993.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.965G>C	p.Ser322Thr	missense	Exon 9 of 13	NP_061866.1
	RIN2	NM_001242581.2		c.1112G>C	p.Ser371Thr	missense	Exon 8 of 12	NP_001229510.1
	RIN2	NM_001378238.1		c.347G>C	p.Ser116Thr	missense	Exon 8 of 12	NP_001365167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.965G>C	p.Ser322Thr	missense	Exon 9 of 13	ENSP00000255006.7
	RIN2	ENST00000484638.1	TSL:1	n.809G>C		non_coding_transcript_exon	Exon 5 of 9
	RIN2	ENST00000440354.2	TSL:1	c.463+14179G>C		intron	N/A	ENSP00000391239.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.079
Sift	Benign	0.14	T
Sift4G	Benign	0.43	T
Polyphen		0.65	P
Vest4		0.38
MutPred		0.17		Loss of phosphorylation at T321 (P = 0.1176)
MVP		0.29
MPC		0.45
ClinPred		0.66	D
GERP RS		5.6
Varity_R		0.11
gMVP		0.29
Mutation Taster		=92/8	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: rs199693970; hg19: chr20-19955634;