8-2942578-A-G

Variant names:

• chr8-2942578-A-G
• rs746303001
• NM_033225.6:c.10429T>C

Variant summary

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

The NM_033225.6(CSMD1):​c.10429T>C​(p.Ser3477Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3477C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSMD1 NM_033225.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32
• Publications: 0 publications found

Genes affected

CSMD1 (HGNC:14026): (CUB and Sushi multiple domains 1) Predicted to act upstream of or within several processes, including learning or memory; mammary gland branching involved in pregnancy; and reproductive structure development. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD1 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

LOC105377785 (HGNC:):

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=0.114604026).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033225.6. 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
	CSMD1	NM_033225.6	MANE Select	c.10429T>C	p.Ser3477Pro	missense	Exon 69 of 70	NP_150094.5
	LOC105377785	NR_168441.1		n.1167-58427A>G		intron	N/A
	LOC105377785	NR_168442.1		n.2191+15948A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD1	ENST00000635120.2	TSL:5 MANE Select	c.10429T>C	p.Ser3477Pro	missense	Exon 69 of 70	ENSP00000489225.1	Q96PZ7-1
	CSMD1	ENST00000335551.11	TSL:1	c.8635T>C	p.Ser2879Pro	missense	Exon 55 of 56	ENSP00000334828.6	H7BXU2
	CSMD1	ENST00000520002.5	TSL:5	c.10432T>C	p.Ser3478Pro	missense	Exon 70 of 71	ENSP00000430733.1	E5RIG2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.30	T
Sift4G	Benign	0.18	T
Polyphen		0.0040	B
Vest4		0.28
MutPred		0.18		Loss of phosphorylation at S3478 (P = 0.0349)
MVP		0.22
ClinPred		0.50	D
GERP RS		3.2
Varity_R		0.25
gMVP		0.35
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs746303001; hg19: chr8-2800100;