chr17-8312938-C-T

Variant names:

• chr17-8312938-C-T
• rs138521691
• NM_173728.4:c.618C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_173728.4(ARHGEF15):​c.618C>T​(p.Cys206Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,579,228 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: ARHGEF15 NM_173728.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.309
• Publications: 1 publications found

Genes affected

ARHGEF15 (HGNC:15590): (Rho guanine nucleotide exchange factor 15) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

ARHGEF15 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000226871 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-8312938-C-T is Benign according to our data. Variant chr17-8312938-C-T is described in ClinVar as Benign. ClinVar VariationId is 412672.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.309 with no splicing effect.
• BS2: High AC in GnomAd4 at 235 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173728.4. 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
	ARHGEF15	NM_173728.4	MANE Select	c.618C>T	p.Cys206Cys	synonymous	Exon 3 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.618C>T	p.Cys206Cys	synonymous	Exon 3 of 16	NP_079290.1	O94989

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.618C>T	p.Cys206Cys	synonymous	Exon 3 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.618C>T	p.Cys206Cys	synonymous	Exon 3 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.618C>T	p.Cys206Cys	synonymous	Exon 3 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00140 AC: 305 AN: 218596 AF XY: 0.00147

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000806

Gnomad ASJ exome AF: 0.000142

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00231 AC: 3295 AN: 1426980 Hom.: 5 Cov.: 33 AF XY: 0.00226 AC XY: 1598 AN XY: 705748

African (AFR) AF: 0.000273 AC: 9 AN: 33002

American (AMR) AF: 0.000941 AC: 40 AN: 42504

Ashkenazi Jewish (ASJ) AF: 0.000214 AC: 5 AN: 23416

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39468

South Asian (SAS) AF: 0.00169 AC: 135 AN: 79732

European-Finnish (FIN) AF: 0.00101 AC: 50 AN: 49466

Middle Eastern (MID) AF: 0.00143 AC: 8 AN: 5592

European-Non Finnish (NFE) AF: 0.00271 AC: 2963 AN: 1094810

Other (OTH) AF: 0.00142 AC: 84 AN: 58990

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152248 Hom.: 0 Cov.: 31 AF XY: 0.00136 AC XY: 101 AN XY: 74448

African (AFR) AF: 0.000481 AC: 20 AN: 41542

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00265 AC: 180 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00136

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ARHGEF15-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.1
DANN	Benign	0.56
PhyloP100		-0.31
PromoterAI		0.0074	Neutral
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs138521691; hg19: chr17-8216256;