chr6-25539987-C-G

Variant names:

• chr6-25539987-C-G
• rs201096469
• NM_017640.6:c.2237C>G

Variant summary

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

The NM_017640.6(CARMIL1):​c.2237C>G​(p.Ala746Gly) 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. A746V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CARMIL1 NM_017640.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• Publications: 2 publications found

Genes affected

CARMIL1 (HGNC:21581): (capping protein regulator and myosin 1 linker 1) Involved in several processes, including actin filament network formation; plasma membrane bounded cell projection organization; and positive regulation of cellular component organization. Located in several cellular components, including lamellipodium; macropinosome; and nuclear speck. [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=0.17944744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017640.6. 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
	CARMIL1	NM_017640.6	MANE Select	c.2237C>G	p.Ala746Gly	missense	Exon 26 of 37	NP_060110.4
	CARMIL1	NM_001173977.2		c.2237C>G	p.Ala746Gly	missense	Exon 26 of 37	NP_001167448.1	A0A8V8TRE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARMIL1	ENST00000329474.7	TSL:1 MANE Select	c.2237C>G	p.Ala746Gly	missense	Exon 26 of 37	ENSP00000331983.6	Q5VZK9-1
	CARMIL1	ENST00000865798.1		c.2237C>G	p.Ala746Gly	missense	Exon 26 of 38	ENSP00000535857.1
	CARMIL1	ENST00000911480.1		c.2237C>G	p.Ala746Gly	missense	Exon 27 of 38	ENSP00000581539.1

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	0.071
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.93	T
PhyloP100		2.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.092
Sift	Benign	0.18	T
Sift4G	Benign	0.41	T
Polyphen		0.61	P
Vest4		0.34
MutPred		0.25		Loss of stability (P = 0.0832)
MVP		0.12
MPC		0.30
ClinPred		0.49	T
GERP RS		3.8
Varity_R		0.048
gMVP		0.31
Mutation Taster		=92/8	polymorphism

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

dbSNP: rs201096469; hg19: chr6-25540215;