10-110919546-T-G

Variant names:

• chr10-110919546-T-G
• rs1203298501
• NM_001324336.2:c.-235+105T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001324336.2(SHOC2):​c.-235+105T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.24 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00086 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHOC2 NM_001324336.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.260
• Publications: 1 publications found

Genes affected

SHOC2 (HGNC:15454): (SHOC2 leucine rich repeat scaffold protein) This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

BBIP1 (HGNC:28093): (BBSome interacting protein 1) This gene encodes one of eight proteins that form the BBSome complex and is essential for its assembly. The BBSome complex is involved in trafficking signal receptors to and from the cilia. Mutations in this gene result in Bardet-Biedl syndrome 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

BBIP1 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 18

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324336.2. 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
	SHOC2	NM_001324336.2		c.-235+105T>G		intron	N/A	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_007373.4	MANE Select	c.-346T>G		upstream_gene	N/A	NP_031399.2
	SHOC2	NM_001324337.2		c.-531T>G		upstream_gene	N/A	NP_001311266.1	Q9UQ13-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	ENST00000688928.1		c.-235+105T>G		intron	N/A	ENSP00000509273.1	Q9UQ13-1
	SHOC2	ENST00000902509.1		c.-235+1481T>G		intron	N/A	ENSP00000572568.1
	SHOC2	ENST00000902510.1		c.-235+549T>G		intron	N/A	ENSP00000572569.1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 3868 AN: 15810 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.000858 AC: 13 AN: 15150 Hom.: 0 Cov.: 0 AF XY: 0.000525 AC XY: 4 AN XY: 7616

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 418

American (AMR) AF: 0.00 AC: 0 AN: 442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 532

East Asian (EAS) AF: 0.00 AC: 0 AN: 1420

South Asian (SAS) AF: 0.00 AC: 0 AN: 398

European-Finnish (FIN) AF: 0.00166 AC: 3 AN: 1810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 72

European-Non Finnish (NFE) AF: 0.000882 AC: 8 AN: 9070

Other (OTH) AF: 0.00202 AC: 2 AN: 988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.245 AC: 3877 AN: 15844 Hom.: 0 Cov.: 0 AF XY: 0.234 AC XY: 1665 AN XY: 7124

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.235 AC: 954 AN: 4062

American (AMR) AF: 0.205 AC: 336 AN: 1640

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 122 AN: 428

East Asian (EAS) AF: 0.195 AC: 53 AN: 272

South Asian (SAS) AF: 0.186 AC: 73 AN: 392

European-Finnish (FIN) AF: 0.223 AC: 247 AN: 1110

Middle Eastern (MID) AF: 0.385 AC: 10 AN: 26

European-Non Finnish (NFE) AF: 0.264 AC: 2021 AN: 7668

Other (OTH) AF: 0.238 AC: 51 AN: 214

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Noonan syndrome-like disorder with loose anagen hair 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		-0.26
PromoterAI		-0.063	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1203298501; hg19: chr10-112679304;