chr10-111007515-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007373.4(SHOC2):​c.1162-16T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SHOC2
NM_007373.4 splice_polypyrimidine_tract, intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.525
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
Variant 10-111007515-T-G is Benign according to our data. Variant chr10-111007515-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 260160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000466 (71/152330) while in subpopulation AFR AF= 0.00159 (66/41586). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 71 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SHOC2NM_007373.4 linkuse as main transcriptc.1162-16T>G splice_polypyrimidine_tract_variant, intron_variant ENST00000369452.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SHOC2ENST00000369452.9 linkuse as main transcriptc.1162-16T>G splice_polypyrimidine_tract_variant, intron_variant 1 NM_007373.4 P1Q9UQ13-1

Frequencies

GnomAD3 genomes
AF:
0.000466
AC:
71
AN:
152212
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00159
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251340
Hom.:
0
AF XY:
0.0000810
AC XY:
11
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00129
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461014
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
726834
show subpopulations
Gnomad4 AFR exome
AF:
0.000957
Gnomad4 AMR exome
AF:
0.0000671
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:
0.00
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.000466
AC:
71
AN:
152330
Hom.:
0
Cov.:
31
AF XY:
0.000564
AC XY:
42
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00159
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000453

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 09, 2019Variant summary: SHOC2 c.1162-16T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.5e-05 in 251340 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 52 fold of the estimated maximal expected allele frequency for a pathogenic variant in SHOC2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. A ClinVar submitter (submission after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
RASopathy Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.66
CADD
Benign
9.0
DANN
Benign
0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376859485; hg19: chr10-112767273; API