20-19975029-C-T

Variant names:

• chr20-19975029-C-T
• NM_018993.4:c.1004C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018993.4(RIN2):​c.1004C>T​(p.Pro335Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RIN2 NM_018993.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34933886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.1004C>T	p.Pro335Leu	missense_variant	Exon 9 of 13	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.1004C>T	p.Pro335Leu	missense_variant	Exon 9 of 13	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000440354.2	c.463+14218C>T		intron_variant	Intron 4 of 7	1		ENSP00000391239.2
RIN2	ENST00000484638.1	n.848C>T		non_coding_transcript_exon_variant	Exon 5 of 9	1
RIN2	ENST00000648440.1	c.1004C>T	p.Pro335Leu	missense_variant	Exon 8 of 12			ENSP00000498085.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461260 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	.;D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0030	.;D
Polyphen		1.0	D;.
Vest4		0.56
MutPred		0.23		Loss of loop (P = 0.0073);.;
MVP		0.53
MPC		0.70
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.41
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-19955673;