chr16-46581923-C-T

Variant names:

• chr16-46581923-C-T
• NM_024745.5:c.1825G>A

Variant summary

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

The NM_024745.5(SHCBP1):​c.1825G>A​(p.Glu609Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SHCBP1 NM_024745.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99
• Publications: 0 publications found

Genes affected

SHCBP1 (HGNC:29547): (SHC binding and spindle associated 1) Predicted to enable SH2 domain binding activity. Predicted to be involved in fibroblast growth factor receptor signaling pathway and regulation of neural precursor cell proliferation. Predicted to be located in cytoplasm; midbody; and spindle. [provided by Alliance of Genome Resources, Apr 2022]

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=0.21069822).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024745.5. 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
	SHCBP1	NM_024745.5	MANE Select	c.1825G>A	p.Glu609Lys	missense	Exon 13 of 13	NP_079021.4
	SHCBP1	NM_001324318.2		c.1711G>A	p.Glu571Lys	missense	Exon 13 of 13	NP_001311247.1
	SHCBP1	NM_001324319.2		c.1591G>A	p.Glu531Lys	missense	Exon 12 of 12	NP_001311248.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHCBP1	ENST00000303383.8	TSL:1 MANE Select	c.1825G>A	p.Glu609Lys	missense	Exon 13 of 13	ENSP00000306473.3	Q8NEM2
	SHCBP1	ENST00000939745.1		c.1657G>A	p.Glu553Lys	missense	Exon 12 of 12	ENSP00000609804.1
	SHCBP1	ENST00000567698.1	TSL:2	n.525G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.049
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.10
Sift	Benign	0.25	T
Sift4G	Benign	0.16	T
Polyphen		0.23	B
Vest4		0.38
MutPred		0.28		Gain of ubiquitination at E609 (P = 0.0121)
MVP		0.38
MPC		0.28
ClinPred		0.52	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.53

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

hg19: chr16-46615835; COSMIC: COSV57650456;