8-3408068-C-G

Variant names:

• chr8-3408068-C-G
• rs10088378
• NM_033225.6:c.1902G>C

Variant summary

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

The NM_033225.6(CSMD1):​c.1902G>C​(p.Gln634His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q634R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSMD1 NM_033225.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSMD1	NM_033225.6	c.1902G>C	p.Gln634His	missense_variant	Exon 14 of 70	ENST00000635120.2	NP_150094.5
CSMD1	XM_011534752.3	c.1902G>C	p.Gln634His	missense_variant	Exon 14 of 69		XP_011533054.1
CSMD1	XM_017013731.2	c.1902G>C	p.Gln634His	missense_variant	Exon 14 of 64		XP_016869220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSMD1	ENST00000635120.2	c.1902G>C	p.Gln634His	missense_variant	Exon 14 of 70	5	NM_033225.6	ENSP00000489225.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461670 Hom.: 0 Cov.: 61 AF XY: 0.00 AC XY: 0 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.;.;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;.;D;D;.;D
M_CAP	Benign	0.0093	T
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.
PhyloP100		0.42
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.0	.;D;.;.;D;.
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;D;.;.;D;.
Sift4G	Uncertain	0.053	T;D;D;D;D;D
Vest4		0.0
ClinPred		0.90	D
GERP RS		2.4
Varity_R		0.32
gMVP		0.57
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs10088378; hg19: chr8-3265590;